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1. Drivers of change in Arctic fjord socio-ecological systems: Examples from the European Arctic

Author

Robert Schlegel, Inka Bartsch, Kai Bischof, Lill Rastad Bjørst, Halvor Dannevig, Nora Diehl, Pedro Duarte, Grete K. Hovelsrud, Thomas Juul-Pedersen, Anaïs Lebrun, Laurène Merillet, Cale Miller, Carina Ren, Mikael Sejr, Janne E. Søreide, Tobias R. Vonnahme, and Jean-Pierre Gattuso

Subjects
Arctic fjords, climate change, social science, marine science, socio-ecological processes, Harbors and coast protective works. Coastal engineering. Lighthouses, TC203-380, Oceanography, GC1-1581
Abstract

Fjord systems are transition zones between land and sea, resulting in complex and dynamic environments. They are of particular interest in the Arctic as they harbour ecosystems inhabited by a rich range of species and provide many societal benefits. The key drivers of change in the European Arctic (i.e., Greenland, Svalbard, and Northern Norway) fjord socio-ecological systems are reviewed here, structured into five categories: cryosphere (sea ice, glacier mass balance, and glacial and riverine discharge), physics (seawater temperature, salinity, and light), chemistry (carbonate system, nutrients), biology (primary production, biomass, and species richness), and social (governance, tourism, and fisheries). The data available for the past and present state of these drivers, as well as future model projections, are analysed in a companion paper. Changes to the two drivers at the base of most interactions within fjords, seawater temperature and glacier mass balance, will have the most significant and profound consequences on the future of European Arctic fjords. This is because even though governance may be effective at mitigating/adapting to local disruptions caused by the changing climate, there is possibly nothing that can be done to halt the melting of glaciers, the warming of fjord waters, and all of the downstream consequences that these two changes will have. This review provides the first transdisciplinary synthesis of the interactions between the drivers of change within Arctic fjord socio-ecological systems. Knowledge of what these drivers of change are, and how they interact with one another, should provide more expedient focus for future research on the needs of adapting to the changing Arctic.

Published
2023
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2. Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol

Author

Laurence S Magder, PJ Devereaux, Diane Smith, Laurence Magder, David J Warwick, Samuel Z Goldhaber, Jay S Magaziner, James A Browne, John Eikelboom, Rebecca Baron, Patrick Heagerty, Stephen L Kates, Vincent D Pellegrini, Jr, John William Eikelboom, C McCollister Evarts, Patricia D Franklin, Kevin L Garvin, Richard Iorio, Carol Ann Lambourne, Jay Magaziner, Eric M Cohen, Charles M Davis, Navin D Fernando, Kevin B Fricka, Richard J Friedman, Kevin L. Garvin, Michael S Kain, Brent A Lanting, Brock A Lindsey, William J Maloney, Robert M Molloy, Michael A Mont, Wayne E Moschetti, James Nace, Charles L Nelson, Kevin I Perry, James D Slover, Mark J Spangehl, Lawrence M Specht, Scott M Sporer, Robert S Sterling, Zeke J Walton, William L Healy, Charles W Francis, Vincent D Pellegrini, Monica Baczko, Carol A Lambourne, Brook I Martin, Ronald Blankstein, Carolyn Come, Jean Connors, Raymond Kwong, Greg Piazza, Rachel Rosovsky, Aaron Waxman, Roger Bulger, Ruth Bulger, Mary Beth Crummer, Debra Hamilton, Connie Persels, Robert Schlegel, Sally Seeley, Mitchell Thompson, Teresa Bordeaux, Kathryn Z Mikkelsen, and Lisa K Moores

Subjects
Medicine
Abstract

Introduction More than 1 million elective total hip and knee replacements are performed annually in the USA with 2% risk of clinical pulmonary embolism (PE), 0.1%–0.5% fatal PE, and over 1000 deaths. Antithrombotic prophylaxis is standard of care but evidence is limited and conflicting. We will compare effectiveness of three commonly used chemoprophylaxis agents to prevent all-cause mortality (ACM) and clinical venous thromboembolism (VTE) while avoiding bleeding complications.Methods and analysis Pulmonary Embolism Prevention after HiP and KneE Replacement is a large randomised pragmatic comparative effectiveness trial with non-inferiority design and target enrolment of 20 000 patients comparing aspirin (81 mg two times a day), low-intensity warfarin (INR (International Normalized Ratio) target 1.7–2.2) and rivaroxaban (10 mg/day). The primary effectiveness outcome is aggregate of VTE and ACM, primary safety outcome is clinical bleeding complications, and patient-reported outcomes are determined at 1, 3 and 6 months. Primary data analysis is per protocol, as preferred for non-inferiority trials, with secondary analyses adherent to intention-to-treat principles. All non-fatal outcomes are captured from patient and clinical reports with independent blinded adjudication. Study design and oversight are by a multidisciplinary stakeholder team including a 10-patient advisory board.Ethics and dissemination The Institutional Review Board of the Medical University of South Carolina provides central regulatory oversight. Patients aged 21 or older undergoing primary or revision hip or knee replacement are block randomised by site and procedure; those on chronic anticoagulation are excluded. Recruitment commenced at 30 North American centres in December 2016. Enrolment currently exceeds 13 500 patients, representing 33% of those eligible at participating sites, and is projected to conclude in July 2024; COVID-19 may force an extension. Results will inform antithrombotic choice by patients and other stakeholders for various risk cohorts, and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants.Trial registration NCT02810704.

Published
2022
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3. Assistant Principal Balancing Act: Making Sense of Social Justice Leadership in a High-Stakes Testing and Accountability Environment

Author

Robert Schlegel

Abstract

The purpose of this study was to examine variation in assistant principal (AP) social justice beliefs and high-stakes accountability perceptions and explore how APs balance accountability policies while addressing social justice issues in their schools. 79 assistant principals participated in a phase 1 survey with 10 APs selected to participate in phase 2 interviews. Findings revealed divergent AP views across social justice and accountability beliefs. APs are not a monolithic block, but individuals with complex histories, working in distinct organizational contexts that shape their ongoing sensemaking and nuanced perspectives regarding social justice leadership and high-stakes testing accountability. Findings drove recommendations for policy, practice, and future research by connecting what APs shared regarding leadership balancing actions that support social justice goals and mitigate impacts of high-stakes testing. Policy recommendations include reducing frequency of testing, development of alternative authentic assessments, and redesigning more robust measures of school-based accountability. Recommendations for practice include continued support for APs beyond initial certification, democratic leadership practices by APs, and more professional development that address issues of marginalization. Recommendations for future research include research to investigate relationships between schools with more students with disabilities and APs' social justice beliefs, and AP mentoring and rotational assignments. The study highlighted the complexity and ambiguity of the assistant principal position, the complicated, nuanced, and ongoing sensemaking of assistant principals, their importance at the forefront of campus leadership, and the impact these often-unnoticed school leaders have on their students, teachers, schools, and communities. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Published
2024

5. Correction: Gene Expression Ratios Lead to Accurate and Translatable Predictors of DR5 Agonism across Multiple Tumor Lineages.

Author

Anupama Reddy, Joseph D Growney, Nick S Wilson, Caroline M Emery, Jennifer A Johnson, Rebecca Ward, Kelli A Monaco, Joshua Korn, John E Monahan, Mark D Stump, Felipa A Mapa, Christopher J Wilson, Janine Steiger, Jebediah Ledell, Richard J Rickles, Vic E Myer, Seth A Ettenberg, Robert Schlegel, William R Sellers, Heather A Huet, and Joseph Lehár

Subjects
Medicine, Science
Published
2016
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6. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies.

Author

Rocio Vicario, Vicente Peg, Beatriz Morancho, Mariano Zacarias-Fluck, Junjie Zhang, Águeda Martínez-Barriocanal, Alexandra Navarro Jiménez, Claudia Aura, Octavio Burgues, Ana Lluch, Javier Cortés, Paolo Nuciforo, Isabel T Rubio, Elisabetta Marangoni, James Deeds, Markus Boehm, Robert Schlegel, Josep Tabernero, Rebecca Mosher, and Joaquín Arribas

Subjects
Medicine, Science
Abstract

A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.

Published
2015
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7. Gene Expression Ratios Lead to Accurate and Translatable Predictors of DR5 Agonism across Multiple Tumor Lineages.

Author

Anupama Reddy, Joseph D Growney, Nick S Wilson, Caroline M Emery, Jennifer A Johnson, Rebecca Ward, Kelli A Monaco, Joshua Korn, John E Monahan, Mark D Stump, Felipa A Mapa, Christopher J Wilson, Janine Steiger, Jebediah Ledell, Richard J Rickles, Vic E Myer, Seth A Ettenberg, Robert Schlegel, William R Sellers, Heather A Huet, and Joseph Lehár

Subjects
Medicine, Science
Abstract

Death Receptor 5 (DR5) agonists demonstrate anti-tumor activity in preclinical models but have yet to demonstrate robust clinical responses. A key limitation may be the lack of patient selection strategies to identify those most likely to respond to treatment. To overcome this limitation, we screened a DR5 agonist Nanobody across >600 cell lines representing 21 tumor lineages and assessed molecular features associated with response. High expression of DR5 and Casp8 were significantly associated with sensitivity, but their expression thresholds were difficult to translate due to low dynamic ranges. To address the translational challenge of establishing thresholds of gene expression, we developed a classifier based on ratios of genes that predicted response across lineages. The ratio classifier outperformed the DR5+Casp8 classifier, as well as standard approaches for feature selection and classification using genes, instead of ratios. This classifier was independently validated using 11 primary patient-derived pancreatic xenograft models showing perfect predictions as well as a striking linearity between prediction probability and anti-tumor response. A network analysis of the genes in the ratio classifier captured important biological relationships mediating drug response, specifically identifying key positive and negative regulators of DR5 mediated apoptosis, including DR5, CASP8, BID, cFLIP, XIAP and PEA15. Importantly, the ratio classifier shows translatability across gene expression platforms (from Affymetrix microarrays to RNA-seq) and across model systems (in vitro to in vivo). Our approach of using gene expression ratios presents a robust and novel method for constructing translatable biomarkers of compound response, which can also probe the underlying biology of treatment response.

Published
2015
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8. MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

Author

Yubao Wang, Young-Mi Lee, Lukas Baitsch, Alan Huang, Yi Xiang, Haoxuan Tong, Ana Lako, Thanh Von, Christine Choi, Elgene Lim, Junxia Min, Li Li, Frank Stegmeier, Robert Schlegel, Michael J Eck, Nathanael S Gray, Timothy J Mitchison, and Jean J Zhao

Subjects
MELK, basal-like breast cancer, triple-negative breast cancer, FoxM1, targeted therapy, Medicine, Science, Biology (General), QH301-705.5
Abstract

Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.

Published
2014
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9. RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth.

Author

Beat Nyfeler, Yan Chen, Xiaoyan Li, Maria Pinzon-Ortiz, Zuncai Wang, Anupama Reddy, Elina Pradhan, Rita Das, Joseph Lehár, Robert Schlegel, Peter M Finan, Z Alexander Cao, Leon O Murphy, and Alan Huang

Subjects
Medicine, Science
Abstract

The mammalian target of rapamycin (mTOR) is regulated by oncogenic growth factor signals and plays a pivotal role in controlling cellular metabolism, growth and survival. Everolimus (RAD001) is an allosteric mTOR inhibitor that has shown marked efficacy in certain cancers but is unable to completely inhibit mTOR activity. ATP-competitive mTOR inhibitors such as NVP-BEZ235 can block rapamycin-insensitive mTOR readouts and have entered clinical development as anti-cancer agents. Here, we show the degree to which RAD001 and BEZ235 can be synergistically combined to inhibit mTOR pathway activation, cell proliferation and tumor growth, both in vitro and in vivo. RAD001 and BEZ235 synergized in cancer lines representing different lineages and genetic backgrounds. Strong synergy is seen in neuronal, renal, breast, lung, and haematopoietic cancer cells harboring abnormalities in PTEN, VHL, LKB1, Her2, or KRAS. Critically, in the presence of RAD001, the mTOR-4EBP1 pathway and tumorigenesis can be fully inhibited using lower doses of BEZ235. This is relevant since RAD001 is relatively well tolerated in patients while the toxicity profiles of ATP-competitive mTOR inhibitors are currently unknown.

Published
2012
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11. Supplementary Figure 4 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 60K, Linear correlation observed between tumor growth inhibition (% T/C) or tumor regression and the fraction of time over the in vivo S473P-Akt IC80 in different cancer cell line-derived tumor xenografts implanted in nude mice (represented as dots) and nude rats (represented as triangles) following NVP-BYL719 treatment (R2=0.77, p

Published
2023

12. Supplementary Figure 6 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 504K

Published
2023

13. Data from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kα may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Kα and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose- and time-dependent inhibition of PI3Kα signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials. Mol Cancer Ther; 13(5); 1117–29. ©2014 AACR.

Published
2023

14. Supplementary Figure 3 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 215K

Published
2023

15. Supplementary Figure 3 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

TSC2 immunohistochemistry assay validation and analysis of HCC xenograft and primary tumors. (A) TSC2 immunohistochemistry (IHC) assay with HCC cell lines. (B) TSC2 IHC assay with HCC xenograft tumors. (C) TSC2 expression by IHC assay in HCC xenografts and their corresponding primary tumors.

Published
2023

16. Supplementary Figure 4 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

Race distribution of HCC patients in EVOLVE-1 trial. Percentage of Caucasian, Asian and other race in different groups of EVOLVE-1 patients (A) and TSC2 IHC H-score ranges (B).

Published
2023

17. Supplementary Figure 7 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 579K

Published
2023

18. Supplementary Figure 2 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

Mechanisms of TSC2 loss in HCC cell lines and xenografts. (A) Taqman RT-PCR analysis of TSC1 and TSC2 mRNA levels in HCC cell lines. (B) Taqman RT-PCR analysis of MZB1, TSC1 and TSC2 mRNA levels in TSC2-null Li-7 cells treated with epigenetic inhibitors. (C) Taqman RT-PCR analysis and (D) immunoblot analysis of TSC2 G305V mutant in HEK293T cells.

Published
2023

19. Supplementary Figure 4 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 766K

Published
2023

20. Supplementary Table 4 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

Genetic characterization of 35 established HCC PTX models by targeted DNA sequencing (Excel file).

Published
2023

22. Supplementary Figure Legends, Supplementary Table Legends, and Supplementary Tables 1 through 7 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 129K, Legends for Supplementary Figures 1 through 4 and Supplementary Tables 1 through 7. Supplementary Table 1. Determination of NVP-BYL719 in vitro effects on human protein kinases. Supplementary Table 2. Activity profile of NVP-BYL719 in the Invitrogen Kinase panel. Supplementary Table 3. Activity profile of NVP-BYL719 in the Ambit Kinase panel. Supplementary Table 4. NVP-BYL719 Kd (nmol/L) determination in the Ambit Kinase panel for the hits found to be inhibited >90%. Supplementary Table 5. NVP-BYL719 anti-tumor effects in diverse cancer cell line-derived xenograft models. Supplementary Table 6. CCLE cell lines responsive to NVP-BYL719. Supplementary Table 7 Anti-tumor effect of NVP-BYL719 in patient-derived xenograft models carrying PIK3CA genetic alterations.

Published
2023

23. Supplementary Table S3 from Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

Author

Vincent A. Miller, Philip J. Stephens, Malte Peters, Eric Collisson, Jeffrey S. Ross, Deborah Morosini, Roman Yelensky, Doron Lipson, Robert Schlegel, Joel Greshock, Jared White, Steven Roels, Eric M. Sanford, Caitlin McMahon, Depinder Khaira, Adrienne Johnson, Joel Greenbowe, Kyle A. Gowen, Alex Fichtenholtz, Rachel Erlich, Julia A. Elvin, Alan Huang, Savina Jaeger, Zachary R. Chalmers, Tim Brennan, Ravi Salgia, Sai-Hong Ignatius Ou, Rick Hoover, David Jentz, Carrie Lee, Jose A. Bufill, Mikhail Akimov, Todd M. Bauer, Xinyuan Lu, Juliann Chmielecki, Mark Rosenzweig, Siraj M. Ali, and Garrett M. Frampton

Abstract

Genomic alterations in lung adenocarcinoma displayed in Figure 2A.

Published
2023

25. Supplementary Figure Legends, Tables 1 - 3 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

Supplementary Table 1. Quantification of phospho-protein levels in Figure 1B. Supplementary Table 2. Everolimus IC50 and growth inhibition at 1uM in HCC cell lines. Supplementary Table 3. Quantification of phospho-protein levels in Figure 2A.

Published
2023

26. Supplementary Figure 2 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 253K

Published
2023

27. Data from Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

Author

Vincent A. Miller, Philip J. Stephens, Malte Peters, Eric Collisson, Jeffrey S. Ross, Deborah Morosini, Roman Yelensky, Doron Lipson, Robert Schlegel, Joel Greshock, Jared White, Steven Roels, Eric M. Sanford, Caitlin McMahon, Depinder Khaira, Adrienne Johnson, Joel Greenbowe, Kyle A. Gowen, Alex Fichtenholtz, Rachel Erlich, Julia A. Elvin, Alan Huang, Savina Jaeger, Zachary R. Chalmers, Tim Brennan, Ravi Salgia, Sai-Hong Ignatius Ou, Rick Hoover, David Jentz, Carrie Lee, Jose A. Bufill, Mikhail Akimov, Todd M. Bauer, Xinyuan Lu, Juliann Chmielecki, Mark Rosenzweig, Siraj M. Ali, and Garrett M. Frampton

Abstract

Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR.See related commentary by Ma, p. 802.See related article by Paik et al., p. 842.This article is highlighted in the In This Issue feature, p. 783

Published
2023

28. Supplementary Figure 2 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 71K, Rat1-myr-p110alpha (blue), beta (green) or delta (red) cells were treated with increasing concentrations of NVP-BYL719 for 30 minutes. Levels of S473P-Akt in cell extracts were quantified by Reverse Phase Protein Array as described in (18) and plotted as percentage of untreated control cells. The graph illustrates n=3 independent experiments. IC50s (plus/minus) SD and IC80s (plus/minus) SD of n=3 independent experiments are reported..

Published
2023

29. Supplementary Figure 1 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 419K

Published
2023

30. Supplementary Figure 1 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

TSC2 loss in HCC cell lines leads to mTOR activation. (A) Reverse Phase Protein Array (RPPA) analysis of nine HCC cell lines for TSC2 protein levels and phosphorylation levels of S6K1, 4E-BP1, S6 and AKT. (B) Immunoblot of TSC2 wild-type HuH-7 cells treated with inhibitors of PI3K, AKT or MEK. (C) p-S6K1(T389) immunoblot of TSC2-null HCC cell lines treated with varying concentrations of everolimus.

Published
2023

31. Supplementary Figure 8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 727K

Published
2023

32. Supplementary Figure 5 from Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Author

Alan Huang, Robert Schlegel, Andrew X. Zhu, Dalila Sellami, Benjamin H. Lee, Yan Wang, Michael R. Palmer, Marissa N. Balak, Adnan Derti, Manway Liu, David Ruddy, David Yang, Panisa Pochanard, Khee Chee Soo, Richard Ong, David Chen, Stephen L. Chan, Huai-Xiang Hao, and Hung Huynh

Abstract

Model of mTOR activation and everolimus sensitivity caused by TSC2 loss.

Published
2023

33. Supplementary Materials, Tables 1-2, Figure Legends 1-8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 180K

Published
2023

34. Supplementary Figure 3 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 92K, NVP-BYL719 does not inhibit mTOR and PIKKs involved in DNA damage-repair processes. A. TSC1 -/- MEFs cells were grown in a 96-well format and treated for 1 h with increased concentrations of RAD001 or NVP-BYL719 (from 0.5 nmol/L to 10 ?mol/L in 1 third dilution steps) and immediately fixed. S235/236P-RPS6 levels were measured and IC50 determined with the Excel module XLfit. Background (no primary Ab incubated); BL, Baseline. B: TSC1 -/- MEFs cells were treated with increasing concentrations of NVP-BYL719 as indicated or RAD001 at 500 nmol/L or an equivalent DMSO concentration for 30 minutes. Levels of S235/236P-RPS6 and total RPS6 in protein- normalized lysates were detected by Western blot analyzis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL. C: 24 h post seeding, A549 cells were treated at the same time with Actinomycin D (Act D) at a concentration of 5 ?mol/L (an agent used to induce DNA damage), and with increasing concentrations of NVP-BYL719 as indicated or with the vehicle control (DMSO) for 1 h. Levels of S15P-p53 and tubulin in protein-normalized lysates were detected by Western blot analysis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL. D: 24 h post seeding, U2OS cells were pre-treated for 1 h with increased concentrations of NVP-BYL719 or KU55933 a specific small molecular mass inhibitor of ATM (Supplementary reference 1) at a concentration of 10 ?mol/L or with the vehicle control (DMSO). The cells were then irradiated with 15 Gy and re-incubated at 37 degrees C for 1 h and then lysed. Levels of S1981P-ATM in protein- normalized lysates were detected by Western blot analysis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL.

Published
2023

35. Supplementary Figure 1 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 37K, NVP-BYL719 was tested at 10 different concentrations (from 0.5 nmol/L to 10 μmol/L in 1 third dilution steps) against CLK2 (A) and LRRK2 (B). SelectScreenTM Kinase Profiling Service uses XLfit from IDBS to determine the IC50 values (IC50 CLK2=621 nmol/L; IC50 LRRK2=3'220 nmol/L). The dose response curve is curve fit to model number 205 (sigmoidal dose-response model).

Published
2023

36. Supplementary Figure 5 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 532K

Published
2023

37. Supplementary Figures S1-S15 from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells

Author

Joseph Lehár, Giordano Caponigro, Levi A. Garraway, Ensar Halilovic, Joel Greshock, Sébastien Jeay, Jens Wuerthner, Erick Morris, Dale Porter, Robert Schlegel, William R. Sellers, Matthew Zubrowski, Ali Farsidjani, Fred Harbinski, Samuel Ho, Angela Tam, Nicolas Ebel, Stéphane Ferretti, and Thomas Horn

Abstract

From images to synergies (S1); Reproducibility of data from two screens (S2); Single agent responses and selectivity (S3); Screen-wide comparison of Caspase 3/7 activation and growth inhibition (S4); Heatmaps of growth inhibition and Capase 3/7 activation, and examples of broadly synergistic combinations targeting RAS/MAPK and/or PI3K/AKT pathways (S5); Combinations targeting RAS/MAPK and PI3K/AKT pathways at different nodes show similar efficacies (S6); Combinations involving RTKs (S7); Heatmaps of growth inhibition and Capase 3/7 activation, and examples of combinations targeting RAS/MAPK or PI3K/AKT pathways and other cellular processes (S8); Synergies of triple combination increase with synergies of underlying drug pairs (S9); Heatmap of synergies, growth inhibition, and Caspase 3/7 activation for triple combinations after hierarchical clustering (S10); Triple combinations targeting RAS/MAPK and PI3K/AKT pathways (S11); Triple combinations targeting RAS/MAPK and/or PI3K/AKT pathways and other cellular processes (S12); Combination targeting MDM2 and MEK in p53 wild-type models (S13); Sequential treatment of p53 wild-type lines with triple combination targeting MDM2, MEK, and BCL-2/-XL (S14); High order combinations to kill 'robust' cell lines (S15).

Published
2023

38. Supplementary Table S6 from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells

Author

Joseph Lehár, Giordano Caponigro, Levi A. Garraway, Ensar Halilovic, Joel Greshock, Sébastien Jeay, Jens Wuerthner, Erick Morris, Dale Porter, Robert Schlegel, William R. Sellers, Matthew Zubrowski, Ali Farsidjani, Fred Harbinski, Samuel Ho, Angela Tam, Nicolas Ebel, Stéphane Ferretti, and Thomas Horn

Abstract

Summarized results for high-order combinations in DLD-1, RKO, HT-29, and LS-180 cell lines.

Published
2023

39. Supplementary Methods and References from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells

Author

Joseph Lehár, Giordano Caponigro, Levi A. Garraway, Ensar Halilovic, Joel Greshock, Sébastien Jeay, Jens Wuerthner, Erick Morris, Dale Porter, Robert Schlegel, William R. Sellers, Matthew Zubrowski, Ali Farsidjani, Fred Harbinski, Samuel Ho, Angela Tam, Nicolas Ebel, Stéphane Ferretti, and Thomas Horn

Abstract

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Published
2023

40. Data from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells

Author

Joseph Lehár, Giordano Caponigro, Levi A. Garraway, Ensar Halilovic, Joel Greshock, Sébastien Jeay, Jens Wuerthner, Erick Morris, Dale Porter, Robert Schlegel, William R. Sellers, Matthew Zubrowski, Ali Farsidjani, Fred Harbinski, Samuel Ho, Angela Tam, Nicolas Ebel, Stéphane Ferretti, and Thomas Horn

Abstract

Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. Cancer Res; 76(23); 6950–63. ©2016 AACR.

Published
2023

41. Supplementary Table and Figure Legends from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells

Author

Joseph Lehár, Giordano Caponigro, Levi A. Garraway, Ensar Halilovic, Joel Greshock, Sébastien Jeay, Jens Wuerthner, Erick Morris, Dale Porter, Robert Schlegel, William R. Sellers, Matthew Zubrowski, Ali Farsidjani, Fred Harbinski, Samuel Ho, Angela Tam, Nicolas Ebel, Stéphane Ferretti, and Thomas Horn

Abstract

Legend for Supplementary Tables S1-S6 and Supplementary Figures S1-S15.

Published
2023

42. Supplementary Figure 1 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 1 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

43. Supplementary Figure 4 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 4 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

44. Supplementary Figure 3 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 3 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

45. Supplementary Figure 2 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 2 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

46. Supplementary Figure 5 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 5 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

47. Supplementary Table 1 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Table 1 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

48. Supplementary Figure 6 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 6 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

49. Data from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor α (TNFα) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFα signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFα induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFα-mediated apoptosis. [Cancer Res 2007;67(24):11493–8]

Published
2023

50. Supplementary Figure 7 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Author

Leigh Zawel, William R. Sellers, Stephen Fawell, Mark Labow, Robert Schlegel, Yan Chen, Alan Huang, Vadim Iourgenko, Tim Ramsey, Christopher Straub, Mary Tran, Joanna Slisz, David Sage, Jerry Donovan, Guang Yang, Jason Borawski, Yao Yao, Dale Porter, and Alex Gaither

Abstract

Supplementary Figure 7 from A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Published
2023

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