PT  - JOURNAL ARTICLE
AU  - Byers, Lauren Averett
AU  - Diao, Lixia
AU  - Wang, Jing
AU  - Saintigny, Pierre
AU  - Girard, Luc
AU  - Peyton, Michael
AU  - Shen, Li
AU  - Fan, You-Hong
AU  - Giri, Uma
AU  - Tumula, Praveen
AU  - Nilsson, Monique B.
AU  - Gudikote, Jayanthi
AU  - Tran, Hai T.
AU  - Cardnell, Robert JG
AU  - Bearss, David J.
AU  - Warner, Steven L.
AU  - Foulks, Jason M.
AU  - Kanner, Steven B.
AU  - Gandhi, Varsha
AU  - Krett, Nancy L.
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, Kie-Kian
AU  - Mills, Gordon B.
AU  - Hong, Waun Ki
AU  - Weinstein, John N.
AU  - Wistuba, Ignacio I.
AU  - Coombes, Kevin
AU  - Minna, John D.
AU  - Heymach, John V.
TI  - An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance
AID  - 10.1158/1078-0432.CCR-12-1558
DP  - 2012 Oct 22
TA  - Clinical Cancer Research
PG  - clincanres.1558.2012
4099  - http://clincancerres.aacrjournals.org/content/early/2012/10/20/1078-0432.CCR-12-1558.short
4100  - http://clincancerres.aacrjournals.org/content/early/2012/10/20/1078-0432.CCR-12-1558.full
AB  - Purpose: EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study. Methods: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. 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 (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified. Results: Compared with epithelial cells, mesenchymal cells demonstrated 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 towards greater sensitivity to the Axl inhibitor SGI-7079. Furthermore, the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, 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.