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1. Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancerResearch in context

Author: Sehhoon Park, Tae Hee Hong, Soohyun Hwang, Simon Heeke, Carl M. Gay, Jiyeon Kim, Hyun-Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Jong Ho Cho, Yong Soo Choi, Jhingook Kim, Young Mog Shim, Hong Kwan Kim, Lauren Averett Byers, John V. Heymach, Yoon-La Choi, Se-Hoon Lee, and Keunchil Park
Subjects: Small cell lung cancer, Molecular subtype, ASCL1, NEUROD1, POU2F3, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. Methods: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. Findings: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4–3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9–3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). Interpretation: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. Funding: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.
Published: 2024
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2. BRAF v600E–mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study

Author: Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David S. Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Lamki Busaidy, Milind Javle, Lauren Averett Byers, John V. Heymach, Funda Meric-Bernstam, and Vivek Subbiah
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or PFS durations were noted, except for inferior OS in the vemurafenib and paclitaxel and carboplatin trial (P = 0.011; HR, 2.4; 95% CI, 1.22–4.7) and in crossover patients (P = 0.0025; HR, 2.089; 95% CI, 1.2–3.4). Patients naïve to prior BRAF inhibitors had statistically significantly improved OS at 12.6 months compared to 10.4 months in the BRAF therapy refractory group (P = 0.024; HR, 1.69; 95% CI 1.07–2.68). The median PFS was statistically significant between both groups, with 7 months in the BRAF therapy naïve group compared to 4.7 months in the BRAF therapy refractory group (P = 0.016; HR, 1.80; 95% CI 1.11–2.91). The confirmed ORR in the vemurafenib monotherapy trial (28%) was higher than that in the combination trials. Our findings suggest that, compared with vemurafenib monotherapy, combinations of vemurafenib with cytotoxic chemotherapy or with RAF- or mTOR-targeting agents do not significantly extend the OS or PFS of patients who have solid tumors with BRAF V600E mutations. Gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance, balancing toxicity and efficacy with novel trial designs are warranted.
Published: 2023
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3. Triple blockade of Ido-1, PD-L1 and MEK as a potential therapeutic strategy in NSCLC

Author: Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, and Floriana Morgillo
Subjects: Ido-1, Checkpoint inhibitor, Resistance, EMT, Medicine
Abstract: Abstract Background Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination. Methods We analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor. Results In NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment. Conclusions We show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients’ derived three dimensional cultures.
Published: 2022
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4. Selecting Reliable mRNA Expression Measurements Across Platforms Improves Downstream Analysis

Author: Pan Tong, Lixia Diao, Li Shen, Lerong Li, John Victor Heymach, Luc Girard, John D. Minna, Kevin R. Coombes, Lauren Averett Byers, and Jing Wang
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2016

5. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Author: Joshua D. Campbell, Christina Yau, Reanne Bowlby, Yuexin Liu, Kevin Brennan, Huihui Fan, Alison M. Taylor, Chen Wang, Vonn Walter, Rehan Akbani, Lauren Averett Byers, Chad J. Creighton, Cristian Coarfa, Juliann Shih, Andrew D. Cherniack, Olivier Gevaert, Marcos Prunello, Hui Shen, Pavana Anur, Jianhong Chen, Hui Cheng, D. Neil Hayes, Susan Bullman, Chandra Sekhar Pedamallu, Akinyemi I. Ojesina, Sara Sadeghi, Karen L. Mungall, A. Gordon Robertson, Christopher Benz, Andre Schultz, Rupa S. Kanchi, Carl M. Gay, Apurva Hegde, Lixia Diao, Jing Wang, Wencai Ma, Pavel Sumazin, Hua-Sheng Chiu, Ting-Wen Chen, Preethi Gunaratne, Larry Donehower, Janet S. Rader, Rosemary Zuna, Hikmat Al-Ahmadie, Alexander J. Lazar, Elsa R. Flores, Kenneth Y. Tsai, Jane H. Zhou, Anil K. Rustgi, Esther Drill, Ronglei Shen, Christopher K. Wong, Joshua M. Stuart, Peter W. Laird, Katherine A. Hoadley, John N. Weinstein, Myron Peto, Curtis R. Pickering, Zhong Chen, Carter Van Waes, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Paul Spellman, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. : Campbell et al. reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations. These affect squamous cell pathways and programs that provide candidates for therapy. Keywords: genomics, transcriptomics, proteomics, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, bladder carcinoma with squamous differentiation, human papillomavirus
Published: 2018
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6. Development and validation of a prognostic gene-expression signature for lung adenocarcinoma.

Author: Yun-Yong Park, Eun Sung Park, Sang Bae Kim, Sang Cheol Kim, Bo Hwa Sohn, In-Sun Chu, Woojin Jeong, Gordon B Mills, Lauren Averett Byers, and Ju-Seog Lee
Subjects: Medicine, Science
Abstract: Although several prognostic signatures have been developed in lung cancer, their application in clinical practice has been limited because they have not been validated in multiple independent data sets. Moreover, the lack of common genes between the signatures makes it difficult to know what biological process may be reflected or measured by the signature. By using classical data exploration approach with gene expression data from patients with lung adenocarcinoma (n = 186), we uncovered two distinct subgroups of lung adenocarcinoma and identified prognostic 193-gene gene expression signature associated with two subgroups. The signature was validated in 4 independent lung adenocarcinoma cohorts, including 556 patients. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio, 2.4; 95% confidence interval, 1.2 to 4.8; p = 0.01). An integrated analysis of the signature revealed that E2F1 plays key roles in regulating genes in the signature. Subset analysis demonstrated that the gene signature could identify high-risk patients in early stage (stage I disease), and patients who would have benefit of adjuvant chemotherapy. Thus, our study provided evidence for molecular basis of clinically relevant two distinct two subtypes of lung adenocarcinoma.
Published: 2012
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7. Aberrant expression of proteins involved in signal transduction and DNA repair pathways in lung cancer and their association with clinical parameters.

Author: Yong He, Zhen Zhou, Wayne L Hofstetter, Yanbin Zhou, Wenxian Hu, Chengcheng Guo, Li Wang, Wei Guo, Apar Pataer, Arlene M Correa, Yiling Lu, Jing Wang, Lixia Diao, Lauren Averett Byers, Ignacio I Wistuba, Jack A Roth, Stephen G Swisher, John V Heymach, and Bingliang Fang
Subjects: Medicine, Science
Abstract: Because cell signaling and cell metabolic pathways are executed through proteins, protein signatures in primary tumors are useful for identifying key nodes in signaling networks whose alteration is associated with malignancy and/or clinical outcomes. This study aimed to determine protein signatures in primary lung cancer tissues.We analyzed 126 proteins and/or protein phosphorylation sites in case-matched normal and tumor samples from 101 lung cancer patients with reverse-phase protein array (RPPA) assay. The results showed that 18 molecules were significantly different (p
Published: 2012
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8. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial

Author: Tina Cascone, Cheuk H. Leung, Annikka Weissferdt, Apar Pataer, Brett W. Carter, Myrna C. B. Godoy, Hope Feldman, William N. William, Yuanxin Xi, Sreyashi Basu, Jing Jing Sun, Shalini S. Yadav, Frank R. Rojas Alvarez, Younghee Lee, Aditya K. Mishra, Lili Chen, Monika Pradhan, Haiping Guo, Ansam Sinjab, Nicolas Zhou, Marcelo V. Negrao, Xiuning Le, Carl M. Gay, Anne S. Tsao, Lauren Averett Byers, Mehmet Altan, Bonnie S. Glisson, Frank V. Fossella, Yasir Y. Elamin, George Blumenschein, Jianjun Zhang, Ferdinandos Skoulidis, Jia Wu, Reza J. Mehran, David C. Rice, Garrett L. Walsh, Wayne L. Hofstetter, Ravi Rajaram, Mara B. Antonoff, Junya Fujimoto, Luisa M. Solis, Edwin R. Parra, Cara Haymaker, Ignacio I. Wistuba, Stephen G. Swisher, Ara A. Vaporciyan, Heather Y. Lin, Jing Wang, Don L. Gibbons, J. Jack Lee, Nadim J. Ajami, Jennifer A. Wargo, James P. Allison, Padmanee Sharma, Humam Kadara, John V. Heymach, and Boris Sepesi
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)
Published: 2023

9. Supplementary Fig S9 from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Fig S9 and legend
Published: 2023

10. Supplementary Fig S10-S20 from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Figures S10-S20 and figure legends
Published: 2023

11. Supplementary Figures 1-7 and Tables 1 and 2 from AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Author: Khandan Keyomarsi, Lauren Averett Byers, Jing Wang, Kelly K. Hunt, John V. Heymach, Steve Warner, Tuyen N. Bui, Jason P.W. Carey, Youhong Fan, Pan Tong, Lixia Diao, Smruthi Vijayaraghavan, and Kavitha Balaji
Abstract: Supplementary Fig. 1. AXL is a direct mediator of EMT Supplementary Fig. 2. AXL inhibition causes DNA damage and reduces levels of DNA repair markers. Supplementary Fig. 3. AXL knockdown cause DNA damage and decreases gene expression of DNA repair genes Supplementary Fig. 4. AXL inhibition is synergistic with PARP inhibition. Supplementary Fig. 5. AXL inhibition in combination with PARP inhibition causes increased subG1 and G2/M populations Supplementary Fig. 6. Correlation analysis with AXL expression in patient cohorts. Supplementary Fig. 7. AXL expression corresponds to expression of DNA repair proteins and EMT markers in patient cohorts Supplementary Table 1. Doubling time upon AXL knockdown Supplementary Table 2. DNA repair proteins and EMT markers analyzed by Reverse Phase Protein Assay
Published: 2023

12. Data from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR.Read the Commentary on this article by Rosell and Wannesson, p. 769.This article is highlighted in the In This Issue feature, p. 753.
Published: 2023

13. Supplementary Figure S1 from Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Author: Zev A. Wainberg, Lauren Averett Byers, Nicola J. Curtin, Miranda Patterson, Ashleigh Herriott, Joshua W. Henshaw, David C. Smith, John Heymach, Jasgit Sachdev, Stan Kaye, Saeed Rafii, John Glaspy, Rashmi Chugh, Lida Mina, Ramesh K. Ramanathan, and Johann de Bono
Abstract: Supplementary Figure S1. Talazoparib inhibition of PBMC PARP activity.
Published: 2023

14. Table S6 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.
Published: 2023

15. Supplementary Table S1 from CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

Author: Don L. Gibbons, F. Xiao-Feng Qin, John V. Heymach, Ignacio I. Wistuba, Stephen E. Ullrich, Jing Wang, Ethan Dmitrovsky, Vassiliki A. Papadimitrakopoulou, Scott E. Woodman, Lauren Averett Byers, Masanori Kawakami, Jaime Rodriguez-Canales, Jingfen Zhu, Caleb A. Class, Youhong Fan, Carl M. Gay, Brett W. Carter, Weiyi Peng, Ferdinandos Skoulidis, Junna Oba, Pan Tong, Jonathon Roybal, Christin Ungewiss, David H. Peng, Jared J. Fradette, Di Peng, Qiang Zhao, Anfei Huang, Philip L. Lorenzi, Lin Tan, Xi Liu, Tina Cascone, Pamela A. Villalobos, Yanli Li, B. Leticia Rodriguez, Xiaohui Yi, Yongbin Yang, Lixia Diao, and Limo Chen
Abstract: Genes differentially expressed between IgG control and anti-PD-L1 treatment.
Published: 2023

16. Supplementary Table 6 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 35K, IC50 values for AZD2281 and AG01469 after 14d treatment.
Published: 2023

17. Supplementary Methods from Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Author: Zev A. Wainberg, Lauren Averett Byers, Nicola J. Curtin, Miranda Patterson, Ashleigh Herriott, Joshua W. Henshaw, David C. Smith, John Heymach, Jasgit Sachdev, Stan Kaye, Saeed Rafii, John Glaspy, Rashmi Chugh, Lida Mina, Ramesh K. Ramanathan, and Johann de Bono
Abstract: Supplementary Methods includes additional details on these topics: tumors eligible for dose escalation phase; tumors eligible for dose expansion phase; patients enrolled using a local laboratory; study design and participants; additional inclusion criteria; full list of exclusion criteria; study treatment; study procedures; pharmacodynamic (PD) analysis; inhibition of PBMC PARP activity.
Published: 2023

18. Supplementary Table 1 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 54K, Small cell lung cancer cell lines.
Published: 2023

19. Supplementary Table 5 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 61K, mRNA transcripts significantly different between SCLC and NSCLC tumors.
Published: 2023

20. Supplementary Table 4 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 53K, mRNA transcripts significantly different between SCLC and NSCLC cell lines.
Published: 2023

21. Data from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment.Significance:The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355
Published: 2023

22. Supplementary Table 2 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 64K, Non-small cell lung cancer cell lines.
Published: 2023

23. Supplementary Methods and Figure Legend from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 142K.
Published: 2023

24. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494
Published: 2023

25. Supplementary Methods from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Methods
Published: 2023

26. Supplementary Table S1 from Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Author: Zev A. Wainberg, Lauren Averett Byers, Nicola J. Curtin, Miranda Patterson, Ashleigh Herriott, Joshua W. Henshaw, David C. Smith, John Heymach, Jasgit Sachdev, Stan Kaye, Saeed Rafii, John Glaspy, Rashmi Chugh, Lida Mina, Ramesh K. Ramanathan, and Johann de Bono
Abstract: Supplementary Table S1. Dose-response and exposure-response parameters.
Published: 2023

27. Supplementary Methods from AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Author: Khandan Keyomarsi, Lauren Averett Byers, Jing Wang, Kelly K. Hunt, John V. Heymach, Steve Warner, Tuyen N. Bui, Jason P.W. Carey, Youhong Fan, Pan Tong, Lixia Diao, Smruthi Vijayaraghavan, and Kavitha Balaji
Abstract: This file contains the supplementary methods
Published: 2023

28. Supplementary Table 7 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 95K, Antibodies used in reverse-phase protein microarrays
Published: 2023

29. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Supplementary materials and methods, as well as supplementary figures S1-S7.
Published: 2023

30. Supplementary Methods; Figures S1 - S22; Tables S2, S6, S9 - S12 from CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

Author: Don L. Gibbons, F. Xiao-Feng Qin, John V. Heymach, Ignacio I. Wistuba, Stephen E. Ullrich, Jing Wang, Ethan Dmitrovsky, Vassiliki A. Papadimitrakopoulou, Scott E. Woodman, Lauren Averett Byers, Masanori Kawakami, Jaime Rodriguez-Canales, Jingfen Zhu, Caleb A. Class, Youhong Fan, Carl M. Gay, Brett W. Carter, Weiyi Peng, Ferdinandos Skoulidis, Junna Oba, Pan Tong, Jonathon Roybal, Christin Ungewiss, David H. Peng, Jared J. Fradette, Di Peng, Qiang Zhao, Anfei Huang, Philip L. Lorenzi, Lin Tan, Xi Liu, Tina Cascone, Pamela A. Villalobos, Yanli Li, B. Leticia Rodriguez, Xiaohui Yi, Yongbin Yang, Lixia Diao, and Limo Chen
Abstract: Supplementary title page. Figure S1: CD38 on anti-PD-L1 resistant tumor cells is up-regulated, which is associated with tumor progression. Figure S2: anti-PD-L1 resistant tumors demonstrate the distinct mRNA and protein profiling for immune signature, reflecting the upregulation of CD38. Figure S3: PD-1/PD-L1 blockade results in CD38 up-regulation and acquired resistance in KP-derived lung and melanoma transplantation tumors. Figure S4: Tumor-associated PD-L1 promotes tumor growth but PD-L1 knockout cancer cells still form tumors. Figure S5: PD-L1 knockout effect on tumor growth is CD8 T cell-dependent. Figure S6: CD38 up-regulation after anti-PD-L1 treatment is associated with all-trans retinoic acid signaling. Figure S7: IFN-b, which is enriched in anti-PD-L1 treated tumors, up-regulates CD38 expression on multiple cancer cell lines. Figure S8: IRF1, which links ATRA and IFN-b, is upregulated after anti-PD-L1 treatment. Figure S9: IFN-g, TNF-a, IL-2, and IL-1b don''t regulate CD38 expression on lung cancer cells. Figure S10: The anti-PD-L1 resistant tumors demonstrate an immune suppressive microenvironment. Figure S11: CD38 substantially changes in vivo tumor formation of PD-L1KO cancer cells, but does not change in vitro cell growth rate and cell cycle. Figure S12: The elimination of PD-L1KOCD38negative cancer cells is CD8+ T cell dependent. Figure S13: CD38 on tumor cells inhibits CD8+ T cell function and protects tumor cells from CD8+ T cell killing. Figure S14: CD38-mediated CD8+TIL dysfunction is not affected by tumor growth rate/tumor size. Figure S15: CD38 expression in cancer cell lines and patient tissues, which is associated with the differentiated immune features. Figure S16: CD38 or PD-L1 expression is not correlated with overall survival in early-stage lung cancer. Figure S17: Pre-treatment levels of CD38 and PD-L1 expression in NSCLC patients who received anti-PD-1/PD-L1 therapy, as divided by clinical outcome. Figure S18: The effect of cancer immunotherapy by anti-CD38 is CD8 T cell dependent. Figure S19: Combined inhibitors of CD38 and PD-L1 inhibits tumor growth and metastases. Figure S20: The co-inhibition of PD-L1 and CD38 leads to a favorable antitumor immune microenvironment. Figure S21: Sequential treatment of anti-PD-L1 and anti-CD38 results in enhanced immune response in tumor microenvironment. Figure S22: anti-mouse CD38 antibody (NIMR-5) does not directly kill tumor cells through ADCC and CDC, but causes CD38 internalization. Table S2: Tumor immune markers with the greatest differential transcriptional levels after anti-PD-L1 treatment. Table S6: The most changed immune-related genes after anti-PD-L1 treatment. Table S9:The correlation between CD38 and suppressive immune markers in LUAD dataset. Table S10: The correlation between CD38 and suppressive immune markers in LUSC dataset. Table S11: The available NSCLC patients with CD38 and PD-L1 tumor cell IHC staining and responses to anti-PD-1 therapy. Table S12: The co-inhibition effect of PD-L1 and CD38 on tumor growth and metastasis. Supplementary Material and Methods: Reagents, Cells and Mice, CRISPR/Cas9 Editing, Antibody-mediated Cell Depletion, CD8+ T Cell Adoptive Transfer, mRNA Profiling of Murine Tumors, Flow Cytometry, Nanostring Analysis, qRT-PCR and Western Blotting, Liquid Chromatography-Mass Spectrometry (LC-MS) Analysis, Histologic Analysis, ELISA and RPPA, ADCC/CDC and Internalization Assays, Human Samples, Statistics. Supplementary references
Published: 2023

31. Supplementary Figure 1 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 125K, Western blot of total PARP1.
Published: 2023

32. Supplementary Table 3 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Author: John V. Heymach, John D. Minna, John N. Weinstein, Kevin R. Coombes, Gordon B. Mills, Scott M. Lippman, Luc Girard, Ignacio I. Wistuba, Neda Kalhor, Bonnie S. Glisson, Stephanie Weber, James Welsh, Vikas Bhardwaj, Praveen Tumula, Boris Duchemann, Wenbin Liu, Li Shen, Fatemeh Masrorpour, Lixia Diao, You Hong Fan, Michael Peyton, Uma Giri, John Yordy, Pierre Saintigny, Junya Fujimoto, Monique B. Nilsson, Jing Wang, and Lauren Averett Byers
Abstract: PDF file, 83K, Proteins with ≥1.2-fold differential expression between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
Published: 2023

33. Supplementary Figure 1 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 167K, Different probes for the same gene vary within and across microarray platforms
Published: 2023

34. Data from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: Purpose: Epithelial–mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non–small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.Experimental Design: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.Results: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.Conclusion: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype. Clin Cancer Res; 19(1); 279–90. ©2012 AACR.
Published: 2023

35. Supplementary Figure 3 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 66K, CDH1 probes vary in their accuracy and dynamic range
Published: 2023

36. Figure S1 from The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Author: Julien Sage, Kévin Contrepois, Michael P. Snyder, Lauren Averett Byers, Laurent Le Cam, Andrew He, Alexandros P. Drainas, Jun W. Kim, Stuart C. Williamson, Triparna Sen, Siqi Cao, Julia Arand, Maya Gershkovitz, Daniel Hornburg, Garry L. Coles, and Sandra Cristea
Abstract: Related to Figure 1: MEK5 and ERK5 mRNA and protein knock-down inhibits the expansion of SCLC cells in culture
Published: 2023

37. Supplementary Data from The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Author: Julien Sage, Kévin Contrepois, Michael P. Snyder, Lauren Averett Byers, Laurent Le Cam, Andrew He, Alexandros P. Drainas, Jun W. Kim, Stuart C. Williamson, Triparna Sen, Siqi Cao, Julia Arand, Maya Gershkovitz, Daniel Hornburg, Garry L. Coles, and Sandra Cristea
Abstract: The 16 Supplementary Tables in the document provide information (including raw data) related to data throughout the manuscript
Published: 2023

38. Supplementary Figure 5 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 50K, Mesenchymal lines are sensitive to Axl inhibition by SGI-7079
Published: 2023

39. Data from CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

Author: Lauren Averett Byers, Jing Wang, John V. Heymach, Helen Piwnica-Worms, Don L. Gibbons, Julien Sage, John D. Minna, Bonnie S. Glisson, Lerong Li, You Hong Fan, Abena B. Redwood, David S. Shames, Aly Valliani, Sandra Cristea, C. Allison Stewart, Pan Tong, and Triparna Sen
Abstract: Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC. Cancer Res; 77(14); 3870–84. ©2017 AACR.
Published: 2023

40. Data from The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Author: Julien Sage, Kévin Contrepois, Michael P. Snyder, Lauren Averett Byers, Laurent Le Cam, Andrew He, Alexandros P. Drainas, Jun W. Kim, Stuart C. Williamson, Triparna Sen, Siqi Cao, Julia Arand, Maya Gershkovitz, Daniel Hornburg, Garry L. Coles, and Sandra Cristea
Abstract: Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5–ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5–ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5–ERK5–lipid metabolism axis that promotes the growth of SCLC.Significance:This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.
Published: 2023

41. Supplementary Materials and Methods from CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

Author: Lauren Averett Byers, Jing Wang, John V. Heymach, Helen Piwnica-Worms, Don L. Gibbons, Julien Sage, John D. Minna, Bonnie S. Glisson, Lerong Li, You Hong Fan, Abena B. Redwood, David S. Shames, Aly Valliani, Sandra Cristea, C. Allison Stewart, Pan Tong, and Triparna Sen
Abstract: This file contains additional details of materials and methods used in this study like SCLC cell line authentication, targeted knockdown of CHK1 and MYC, PCR, cell viability aasay, cell cycle analysis, generation of tumor models, RPPA and immunofluorescence.
Published: 2023

42. Supplementary Methods from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 175K
Published: 2023

43. Supplementary Table 1 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 214K, The EMT signature genes
Published: 2023

44. Supplementary Table 3 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 71K, Percentage tumor volume compared to control, survival and therapeutic efficacy at days 17 and 38 post-treatment
Published: 2023

45. Supplementary Table 2 from An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Author: John V. Heymach, John D. Minna, Kevin R. Coombes, Ignacio I. Wistuba, John N. Weinstein, Waun K. Hong, Gordon B. Mills, K. Kian Ang, Scott M. Lippman, J. Jack Lee, George R. Blumenschein, Roy S. Herbst, Edward S. Kim, Steven T. Rosen, Nancy Krett, Varsha Gandhi, Steven B. Kanner, Jason M. Foulks, Steven L. Warner, David J. Bearss, Robert J.G. Cardnell, Hai Tran, Jayanthi Gudikote, Monique B. Nilsson, Praveen K. Tumula, Uma Giri, Youhong Fan, Li Shen, Michael Peyton, Luc Girard, Pierre Saintigny, Jing Wang, Lixia Diao, and Lauren Averett Byers
Abstract: PDF file - 51K, EMT status of commonly mutated genes in NSCLC
Published: 2023

46. Supplementary tables from CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

Author: Lauren Averett Byers, Jing Wang, John V. Heymach, Helen Piwnica-Worms, Don L. Gibbons, Julien Sage, John D. Minna, Bonnie S. Glisson, Lerong Li, You Hong Fan, Abena B. Redwood, David S. Shames, Aly Valliani, Sandra Cristea, C. Allison Stewart, Pan Tong, and Triparna Sen
Abstract: This file contains supplementary tables Table S1: Genotypic status of human SCLC cell lines and their sensitivity to LY2606368 Table S2: Pairwise p-value of the syngeneic SCLC in vivo survival data of Figure 3 Table S3: Primers sequence for CHEK1 and GAPDH
Published: 2023

47. Supplementary Methods from The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Author: Julien Sage, Kévin Contrepois, Michael P. Snyder, Lauren Averett Byers, Laurent Le Cam, Andrew He, Alexandros P. Drainas, Jun W. Kim, Stuart C. Williamson, Triparna Sen, Siqi Cao, Julia Arand, Maya Gershkovitz, Daniel Hornburg, Garry L. Coles, and Sandra Cristea
Abstract: Detailed methods
Published: 2023

48. Figures S5 and S6 from The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Author: Julien Sage, Kévin Contrepois, Michael P. Snyder, Lauren Averett Byers, Laurent Le Cam, Andrew He, Alexandros P. Drainas, Jun W. Kim, Stuart C. Williamson, Triparna Sen, Siqi Cao, Julia Arand, Maya Gershkovitz, Daniel Hornburg, Garry L. Coles, and Sandra Cristea
Abstract: Related to Figure 4: Lipidomic profiling of SCLC cells
Published: 2023

49. Data from Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

Author: Lauren Averett Byers, Jing Wang, John V. Heymach, Jennifer Hoff, Youhong Fan, Lerong Li, Lixia Diao, Pan Tong, and Triparna Sen
Abstract: Purpose: Drugs targeting DNA repair and cell-cycle checkpoints have emerged as promising therapies for small-cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations.Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse-phase protein array (RPPA) to identify predictive markers of primary resistance. We further established AZD1775 acquired resistance models to identify mechanism of acquired resistance. Combination regimens were tested to overcome primary and acquired resistance to AZD1775 in in vitro and in vivo SCLC models.Results: High-throughput proteomic profiling demonstrate that SCLC models with primary resistance to AZD1775 express high levels of AXL and phosphorylated S6 and that WEE1/AXL or WEE1/mTOR inhibitor combinations overcome resistance in vitro and in vivo. Furthermore, AXL, independently and via mTOR, activates the ERK pathway, leading to recruitment and activation of another G2-checkpoint protein, CHK1. AZD1775 acquired resistance models demonstrated upregulation of AXL, pS6, and MET, and resistance was overcome with the addition of AXL (TP0903), dual-AXL/MET (cabozantinib), or mTOR (RAD001) inhibitors.Conclusions: AXL promotes resistance to WEE1 inhibition via downstream mTOR signaling and resulting activation of a parallel DNA damage repair pathway, CHK1. These findings suggest rational combinations to enhance the clinical efficacy of AZD1775, which is currently in clinical trials for SCLC and other malignancies. Clin Cancer Res; 23(20); 6239–53. ©2017 AACR.
Published: 2023

50. Supplementary Material from Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

Author: Lauren Averett Byers, Jing Wang, John V. Heymach, Jennifer Hoff, Youhong Fan, Lerong Li, Lixia Diao, Pan Tong, and Triparna Sen
Abstract: This file contains the supplementary figures and figure legends. Figure S1: WEE1 is overexpressed in small cell lung cancer (SCLC) compared with non-small cell lung cancer cell lines, and targeting WEE1 with AZD1775 prevents sub-G1 accumulation of WEE1 in AZD1775-sensitive cells. Figure S2: WEE1 inhibition is synergistic with temozolomide (TMZ) independent of initial sensitivity to WEE1 targeting in small cell lung cancer (SCLC) cell lines. Figure S3: Increased basal expression of members of the mTOR signaling pathway in small cell lung cancer cells showing primary resistance to AZD1775. Figure S4: Co-targeting AXL and mTOR overcomes de novo AZD1775 resistance in small cell lung cancer in vitro. Figure S5: Co-inhibition of AXL and/or mTOR pathway enhances the antitumor efficacy of WEE1 inhibition in small cell lung cancer in vivo. Figure S6: AXL/mTOR signaling activates other DNA repair proteins via the ERK/p90RSK pathway. Figure S7: Generation of models with acquired AZD1775 resistance. Supplementary Materials and Methods - Additional details of materials and methods used in this study like SCLC cell line authentication, targeted knockdown of WEE1 and AXL, PCR, cell viability aasay, cell cycle analysis, RPPA and immunofluorescence. Supplementary tables - Table S1: Genotypic status of human cell lines treated with the WEE1 inhibitor AZD1775. Table S2: Primer sequences for WEE1, AXL, and GAPDH. Table S3: List of primary antibodies.
Published: 2023

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