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

被引：862

作者：

Byers, Lauren Averett ^{[1
]}

Diao, Lixia ^{[2
]}

Wang, Jing ^{[2
]}

Saintigny, Pierre ^{[1
]}

Girard, Luc ^{[10
,11
]}

Peyton, Michael ^{[10
,11
]}

Shen, Li ^{[2
]}

Fan, Youhong ^{[1
]}

Giri, Uma ^{[1
]}

Tumula, Praveen K. ^{[1
]}

Nilsson, Monique B. ^{[1
]}

Gudikote, Jayanthi ^{[1
]}

Tran, Hai ^{[1
]}

Cardnell, Robert J. G. ^{[1
]}

Bearss, David J. ^{[12
]}

Warner, Steven L. ^{[12
]}

Foulks, Jason M. ^{[13
]}

Kanner, Steven B. ^{[13
]}

Gandhi, Varsha ^{[8
]}

Krett, Nancy ^{[14
]}

Rosen, Steven T. ^{[14
]}

Kim, Edward S. ^{[1
]}

Herbst, Roy S. ^{[1
]}

Blumenschein, George R. ^{[1
]}

Lee, J. Jack ^{[3
]}

Lippman, Scott M. ^{[1
]}

Ang, K. Kian ^{[4
]}

Mills, Gordon B. ^{[5
]}

Hong, Waun K. ^{[9
]}

Weinstein, John N. ^{[2
,5
]}

Wistuba, Ignacio I. ^{[6
]}

Coombes, Kevin R. ^{[2
]}

Minna, John D. ^{[10
,11
]}

Heymach, John V. ^{[1
,7
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Head & Neck Med Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA

[10] Univ Texas SW, Hamon Ctr Therapeut Oncol Res, Dallas, TX USA

[11] Univ Texas SW, Simmons Canc Ctr, Dallas, TX USA

[12] Tolero Pharmaceut Inc, Salt Lake City, UT USA

[13] Astex Pharmaceut Inc, Salt Lake City, UT USA

[14] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

来源：

CLINICAL CANCER RESEARCH | 2013年 / 19卷 / 01期

关键词：

GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TRANSCRIPTION FACTOR SNAIL; E-CADHERIN EXPRESSION; EML4-ALK FUSION GENE; TUMOR-CELLS; KINASE INHIBITOR; SENSITIVITY; GEFITINIB; MUTATIONS;

D O I：

10.1158/1078-0432.CCR-12-1558

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. (c) 2012 AACR.

引用

页码：279 / 290

页数：12

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