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

Lauren Averett Byers, Lixia Diao, Jing Wang, Pierre Saintigny, Luc Girard, Michael Peyton, Li Shen, Youhong Fan, Uma Giri, Praveen K. Tumula, Monique B. Nilsson, Jayanthi Gudikote, Hai Tran, Robert J G Cardnell, David J. Bearss, Steven L. Warner, Jason M. Foulks, Steven B. Kanner, Varsha Gandhi, Nancy Krett & 14 others Steven T. Rosen, Edward S. Kim, Roy S. Herbst, George R. Blumenschein, J. Jack Lee, Scott M. Lippman, K. Kian Ang, Gordon B. Mills, Waun K. Hong, John N. Weinstein, Ignacio I. Wistuba, Kevin R. Coombes, John D. Minna, John V. Heymach

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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.

Original languageEnglish (US)
Pages (from-to)279-290
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2013

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Epithelial-Mesenchymal Transition
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Genes
Transcriptome
Lung Neoplasms
Therapeutics
Biomarkers
Epithelial Cells
Cell Line
Tumor Cell Line
Heterografts
Pharmaceutical Preparations
Proteomics
Research Design
Phenotype
Gene Expression
Drug Therapy
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

In: Clinical Cancer Research, Vol. 19, No. 1, 01.01.2013, p. 279-290.

Research output: Contribution to journalArticle

Byers, LA, Diao, L, Wang, J, Saintigny, P, Girard, L, Peyton, M, Shen, L, Fan, Y, Giri, U, Tumula, PK, Nilsson, MB, Gudikote, J, Tran, H, Cardnell, RJG, Bearss, DJ, Warner, SL, Foulks, JM, Kanner, SB, Gandhi, V, Krett, N, Rosen, ST, Kim, ES, Herbst, RS, Blumenschein, GR, Lee, JJ, Lippman, SM, Ang, KK, Mills, GB, Hong, WK, Weinstein, JN, Wistuba, II, Coombes, KR, Minna, JD & Heymach, JV 2013, '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', Clinical Cancer Research, vol. 19, no. 1, pp. 279-290. https://doi.org/10.1158/1078-0432.CCR-12-1558
Byers, Lauren Averett ; Diao, Lixia ; Wang, Jing ; Saintigny, Pierre ; Girard, Luc ; Peyton, Michael ; Shen, Li ; Fan, Youhong ; Giri, Uma ; Tumula, Praveen K. ; Nilsson, Monique B. ; Gudikote, Jayanthi ; Tran, Hai ; Cardnell, Robert J G ; Bearss, David J. ; Warner, Steven L. ; Foulks, Jason M. ; Kanner, Steven B. ; Gandhi, Varsha ; Krett, Nancy ; Rosen, Steven T. ; Kim, Edward S. ; Herbst, Roy S. ; Blumenschein, George R. ; Lee, J. Jack ; Lippman, Scott M. ; Ang, K. Kian ; Mills, Gordon B. ; Hong, Waun K. ; Weinstein, John N. ; Wistuba, Ignacio I. ; Coombes, Kevin R. ; Minna, John D. ; Heymach, John V. / 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. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 1. pp. 279-290.
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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.",
author = "Byers, {Lauren Averett} and Lixia Diao and Jing Wang and Pierre Saintigny and Luc Girard and Michael Peyton and Li Shen and Youhong Fan and Uma Giri and Tumula, {Praveen K.} and Nilsson, {Monique B.} and Jayanthi Gudikote and Hai Tran and Cardnell, {Robert J G} and Bearss, {David J.} and Warner, {Steven L.} and Foulks, {Jason M.} and Kanner, {Steven B.} and Varsha Gandhi and Nancy Krett and Rosen, {Steven T.} and Kim, {Edward S.} and Herbst, {Roy S.} and Blumenschein, {George R.} and Lee, {J. Jack} and Lippman, {Scott M.} and Ang, {K. Kian} and Mills, {Gordon B.} and Hong, {Waun K.} and Weinstein, {John N.} and Wistuba, {Ignacio I.} and Coombes, {Kevin R.} and Minna, {John D.} and Heymach, {John V.}",
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T1 - 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

AU - Byers, Lauren Averett

AU - Diao, Lixia

AU - Wang, Jing

AU - Saintigny, Pierre

AU - Girard, Luc

AU - Peyton, Michael

AU - Shen, Li

AU - Fan, Youhong

AU - Giri, Uma

AU - Tumula, Praveen K.

AU - Nilsson, Monique B.

AU - Gudikote, Jayanthi

AU - Tran, Hai

AU - Cardnell, Robert J G

AU - Bearss, David J.

AU - Warner, Steven L.

AU - Foulks, Jason M.

AU - Kanner, Steven B.

AU - Gandhi, Varsha

AU - Krett, Nancy

AU - Rosen, Steven T.

AU - Kim, Edward S.

AU - Herbst, Roy S.

AU - Blumenschein, George R.

AU - Lee, J. Jack

AU - Lippman, Scott M.

AU - Ang, K. Kian

AU - Mills, Gordon B.

AU - Hong, Waun K.

AU - Weinstein, John N.

AU - Wistuba, Ignacio I.

AU - Coombes, Kevin R.

AU - Minna, John D.

AU - Heymach, John V.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

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