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.

doi:10.1158/1078-0432.ccr-12-1558

Cited by 1,059Lung Cancer Treatments and MutationsCancer Cells and MetastasisHER2/EGFR in Cancer Research

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

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Byers, Lauren Averett, Diao, Lixia, Wang, Jing, Saintigny, Pierre, Girard, Luc, Peyton, Michael, Shen, Li, Fan, Youhong +26 more·2013·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-12-1558PMC PMC3567921

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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. Clin Cancer Res; 19(1); 279–90. ©2012 AACR.

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High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.
“High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.”
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Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway.
“Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway [43, 136–139].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [136]
A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast, ovarian, and lung.
“A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast (81), ovarian (82), and lung (83).”
From Hypoxic control of metastasis (2016) · cites this paper as [83]
AXL inhibition sensitizes drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, EGFR inhibitors, and PI3K inhibitors.
“AXL inhibition has been reported to sensitize drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, epidermal growth factor receptor (EGFR) inhibitors, and PI3K inhibitors”
From Hypoxic control of metastasis (2016) · cites this paper as [83]

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Authors: Byers, L. A., Diao, L., Wang, J., Saintigny, P., Girard, L., Peyton, M., Shen, L., Fan, Y., Giri, U., Tumula, P. K., Nilsson, M. B., Gudikote, J., Tran, H., Cardnell, R. J. G., Bearss, D. J., Warner, S. L., Foulks, J. M., Kanner, S. B., Gandhi, V., Krett, N., Rosen, S. T., Kim, E. S., Herbst, R. S., Blumenschein, G. R., Lee, J. J., Lippman, S. M., Ang, K. K., Mills, G. B., Hong, W. K., Weinstein, J. N., Wistuba, I. I., Coombes, K. R., Minna, J. D., & Heymach, J. V.
Affiliations: Northwestern University (US)
Authors' Affiliations: Departments of 1Thoracic and Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Biostatistics, 4Radiation Oncology, 5Systems Biology, 6Pathology, 7Cancer Biology, and 8Experimental Therapeutics, and 9Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston; 10Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, University of Texas Southwestern, Dallas, Texas; 11Tolero Pharmaceuticals, Inc.; 12Astex Pharmaceuticals, Inc., Salt Lake City, Utah; and 13Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois
Corresponding author: Byers, Lauren Averett
Heymach, John V.
ORCID: Byers, Lauren Averett
Diao, Lixia
Wang, Jing
Saintigny, Pierre
Girard, Luc
Peyton, Michael
Shen, Li
Giri, Uma
Nilsson, Monique B.
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.
Lippman, Scott M.
Mills, Gordon B.
Hong, Waun K.
Weinstein, John N.
Wistuba, Ignacio I.
Coombes, Kevin R.
Minna, John D.
Heymach, John V.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2013-01-01
Volume: 19
Issue: 1
Pages: 279-290
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-12-1558
PMC: PMC3567921
OpenAlex: W2169105660
Cited by: 1,059
References: 44
Citations by year: 2026: 42 · 2025: 55 · 2024: 90 · 2023: 97 · 2022: 106 · 2021: 103 · 2020: 94 · 2019: 71 · 2018: 61 · 2017: 82 · 2016: 74 · 2015: 83 · 2014: 52 · 2013: 46 · 2012: 1
FWCI: 46.91
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P50CA098258, U24CA143883, P50CA070907, R01CA168484, P30CA016672)
National Center for Research Resources (UL1RR024148)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: epithelial-mesenchymal transition, EGFR inhibitor resistance, AXL, erlotinib, non-small cell lung cancer, drug response prediction, mesenchymal phenotype, combination therapy
MeSH terms: Phosphoinositide-3 Kinase Inhibitors, Axl Receptor Tyrosine Kinase, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neoplasm Metastasis, Proto-Oncogene Proteins, Recurrence, Reproducibility of Results, Cluster Analysis, Drug Resistance, Neoplasm, Proteome, Receptor Protein-Tyrosine Kinases, Gene Expression Profiling, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Epithelial-Mesenchymal Transition, ErbB Receptors

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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

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