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19 results on '"Avila, Kimberley"'

2. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Author

Li, Huiyu, Liu, Zhida, Liu, Longchao, Zhang, Hongyi, Han, Chuanhui, Girard, Luc, Park, Hyunsil, Zhang, Anli, Dong, Chunbo, Ye, Jianfeng, Rayford, Austin, Peyton, Michael, Li, Xiaoguang, Avila, Kimberley, Cao, Xuezhi, Hu, Shuiqing, Alam, Md Maksudul, Akbay, Esra A., Solis, Luisa M., Behrens, Carmen, Hernandez-Ruiz, Sharia, Lu, Wei, Wistuba, Ignacio, Heymach, John V., Chisamore, Michael, Micklem, David, Gabra, Hani, Gausdal, Gro, Lorens, James B., Li, Bo, Fu, Yang-Xin, Minna, John D., and Brekken, Rolf A.

Published
2022
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3. Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology

Author

Stewart, C. Allison, Gay, Carl M., Ramkumar, Kavya, Cargill, Kasey R., Cardnell, Robert J., Nilsson, Monique B., Heeke, Simon, Park, Elizabeth M., Kundu, Samrat T., Diao, Lixia, Wang, Qi, Shen, Li, Xi, Yuanxin, Zhang, Bingnan, Della Corte, Carminia Maria, Fan, Youhong, Kundu, Kiran, Gao, Boning, Avila, Kimberley, Pickering, Curtis R., Johnson, Faye M., Zhang, Jianjun, Kadara, Humam, Minna, John D., Gibbons, Don L., Wang, Jing, Heymach, John V., and Byers, Lauren Averett

Published
2021
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4. Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

Author

Deb, Dhruba, Rajaram, Satwik, Larsen, Jill E, Dospoy, Patrick D, Marullo, Rossella, Li, Long Shan, Avila, Kimberley, Xue, Fengtian, Cerchietti, Leandro, Minna, John D, Altschuler, Steven J, and Wu, Lani F

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Lung Cancer, Lung, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Combined Modality Therapy, Humans, Lung Neoplasms, Proto-Oncogene Proteins c-bcl-6, STAT3 Transcription Factor, Signal Transduction, Transfection, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070-81. ©2017 AACR.

Published
2017

5. An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis

Author

Hight, Suzie K., Mootz, Allison, Kollipara, Rahul K., McMillan, Elizabeth, Yenerall, Paul, Otaki, Yoichi, Li, Long-Shan, Avila, Kimberley, Peyton, Michael, Rodriguez-Canales, Jaime, Mino, Barbara, Villalobos, Pamela, Girard, Luc, Dospoy, Patrick, Larsen, Jill, White, Michael A., Heymach, John V., Wistuba, Ignacio I., Kittler, Ralf, and Minna, John D.

Published
2020
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7. Data from Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

Author

Deb, Dhruba, primary, Rajaram, Satwik, primary, Larsen, Jill E., primary, Dospoy, Patrick D., primary, Marullo, Rossella, primary, Li, Long Shan, primary, Avila, Kimberley, primary, Xue, Fengtian, primary, Cerchietti, Leandro, primary, Minna, John D., primary, Altschuler, Steven J., primary, and Wu, Lani F., primary

Published
2023
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8. Legends for supplementary figures from Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

Author

Deb, Dhruba, primary, Rajaram, Satwik, primary, Larsen, Jill E., primary, Dospoy, Patrick D., primary, Marullo, Rossella, primary, Li, Long Shan, primary, Avila, Kimberley, primary, Xue, Fengtian, primary, Cerchietti, Leandro, primary, Minna, John D., primary, Altschuler, Steven J., primary, and Wu, Lani F., primary

Published
2023
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9. Supplementary figures from Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

Author

Deb, Dhruba, primary, Rajaram, Satwik, primary, Larsen, Jill E., primary, Dospoy, Patrick D., primary, Marullo, Rossella, primary, Li, Long Shan, primary, Avila, Kimberley, primary, Xue, Fengtian, primary, Cerchietti, Leandro, primary, Minna, John D., primary, Altschuler, Steven J., primary, and Wu, Lani F., primary

Published
2023
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11. Data from Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations

Author

Yenerall, Paul, primary, Kollipara, Rahul K., primary, Avila, Kimberley, primary, Peyton, Michael, primary, Eide, Christopher A., primary, Bottomly, Daniel, primary, McWeeney, Shannon K., primary, Liu, Yan, primary, Westover, Kenneth D., primary, Druker, Brian J., primary, Minna, John D., primary, and Kittler, Ralf, primary

Published
2023
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13. Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers

Author

Huffman, Kenneth E., primary, Li, Long Shan, additional, Carstens, Ryan, additional, Park, Hyunsil, additional, Girard, Luc, additional, Avila, Kimberley, additional, Wei, Shuguang, additional, Kollipara, Rahul, additional, Timmons, Brenda, additional, Sudderth, Jessica, additional, Bendris, Nawal, additional, Kim, Jiyeon, additional, Villalobos, Pamela, additional, Fujimoto, Junya, additional, Schmid, Sandra, additional, Deberardinis, Ralph J., additional, Wistuba, Ignacio, additional, Heymach, John, additional, Kittler, Ralf, additional, Akbay, Esra A., additional, Posner, Bruce, additional, Wang, Yuzhuo, additional, Lam, Stephen, additional, Kliewer, Steven A., additional, Mangelsdorf, David J., additional, and Minna, John D., additional

Published
2023
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14. Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations

Author

Yenerall, Paul, primary, Kollipara, Rahul K., additional, Avila, Kimberley, additional, Peyton, Michael, additional, Eide, Christopher A., additional, Bottomly, Daniel, additional, McWeeney, Shannon K., additional, Liu, Yan, additional, Westover, Kenneth D., additional, Druker, Brian J., additional, Minna, John D., additional, and Kittler, Ralf, additional

Published
2021
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15. Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

Author

Stewart, C. Allison, primary, Gay, Carl M., additional, Ramkumar, Kavya, additional, Cargill, Kasey R., additional, Cardnell, Robert J., additional, Nilsson, Monique B., additional, Heeke, Simon, additional, Park, Elizabeth M., additional, Kundu, Samrat T., additional, Diao, Lixia, additional, Wang, Qi, additional, Shen, Li, additional, Xi, Yuanxin, additional, Zhang, Bingnan, additional, Della Corte, Carminia Maria, additional, Fan, Youhong, additional, Kundu, Kiran, additional, Gao, Boning, additional, Avila, Kimberley, additional, Pickering, Curtis R., additional, Johnson, Faye M., additional, Zhang, Jianjun, additional, Kadara, Humam, additional, Minna, John D., additional, Gibbons, Don L., additional, Wang, Jing, additional, Heymach, John V., additional, and Byers, Lauren Averett, additional

Published
2020
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16. Abstract 2664: Identification of two small molecules with small cell lung cancer growth inhibition response profiles different from etoposide/topotecan

Author

Mootz, Allison A., primary, Peyton, Michael, additional, Yenerall, Paul, additional, Avila, Kimberley, additional, Huffman, Kenneth, additional, Haruki, Tomohiro, additional, Papari-Zareei, Mahboubeh, additional, Stastny, Victor, additional, Girard, Luc, additional, McMillan, Elizabeth, additional, Roth, Michael, additional, MacMillan, John, additional, Posner, Bruce, additional, White, Michael, additional, Adi, Gazdar, additional, and Minna, John, additional

Published
2018
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17. Abstract 3950: A novel combination therapy targeting BCL6 and phospho-STAT3 defeats intratumor heterogeneity in a subset of non-small cell lung cancers

Author

Deb, Dhruba, primary, Rajaram, Satwik, additional, Larsen, Jill E., additional, Dospoy, Patrick P., additional, Marullo, Rossella, additional, Li, Longshan, additional, Avila, Kimberley, additional, Cerchietti, Leandro, additional, Minna, John D., additional, Wu, Lani F., additional, and Altschuler, Steven J., additional

Published
2017
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18. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1mutant NSCLC through expansion of TCF1+CD8 T cells

Author

Li, Huiyu, Liu, Zhida, Liu, Longchao, Zhang, Hongyi, Han, Chuanhui, Girard, Luc, Park, Hyunsil, Zhang, Anli, Dong, Chunbo, Ye, Jianfeng, Rayford, Austin, Peyton, Michael, Li, Xiaoguang, Avila, Kimberley, Cao, Xuezhi, Hu, Shuiqing, Alam, Md Maksudul, Akbay, Esra A., Solis, Luisa M., Behrens, Carmen, Hernandez-Ruiz, Sharia, Lu, Wei, Wistuba, Ignacio, Heymach, John V., Chisamore, Michael, Micklem, David, Gabra, Hani, Gausdal, Gro, Lorens, James B., Li, Bo, Fu, Yang-Xin, Minna, John D., and Brekken, Rolf A.

Abstract

Mutations in STK11/LKB1in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1(L) mutation into murine lung adenocarcinomas driven by mutant Krasand Trp53loss (KP) resulted in an ICB refractory syngeneic KPLtumor. Mechanistically this occurred because KPLmutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPLtumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1mutant NSCLC.

Published
2022
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19. Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology.

Author

Stewart CA, Gay CM, Ramkumar K, Cargill KR, Cardnell RJ, Nilsson MB, Heeke S, Park EM, Kundu ST, Diao L, Wang Q, Shen L, Xi Y, Zhang B, Della Corte CM, Fan Y, Kundu K, Gao B, Avila K, Pickering CR, Johnson FM, Zhang J, Kadara H, Minna JD, Gibbons DL, Wang J, Heymach JV, and Byers LA

Abstract

COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2 . We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL , resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike., Competing Interests: Competing Interests Statement L.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. J.V.H. serves on advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GSK, Guardant Health, Hengrui, Lilly, Novartis, Spectrum, EMD Serono, and Synta, has research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum and royalties and licensing fees from Spectrum. D.L.G. has served on scientific advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi and Janssen and has received research support from Janssen, Takeda, Ribon Therapeutics, Astellas and AstraZeneca. C.M.G. received research funding from AstraZeneca. Otherwise, there are no pertinent financial or non-financial conflicts of interest to report.

Published
2021
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