Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Zhenfeng Zhang, Jae Cheol Lee, Luping Lin, Victor Olivas, Valerie Au, Thomas Laframboise, Mohamed Abdel-Rahman, Xiaoqi Wang, Alan D. Levine, Jin Kyung Rho, Yun Jung Choi, Chang Min Choi, Sang We Kim, Se Jin Jang, Young Soo Park, Woo Sung Kim, Dae Ho Lee, Jung Shin Lee, Vincent A. Miller, Maria Arcila & 10 others Marc Ladanyi, Philicia Moonsamy, Charles Sawyers, Titus J. Boggon, Patrick C. Ma, Carlota Costa, Miquel Taron, Rafael Rosell, Balazs Halmos, Trever G. Bivona

Research output: Contribution to journalArticle

623 Citations (Scopus)

Abstract

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

Original languageEnglish (US)
Pages (from-to)852-860
Number of pages9
JournalNature Genetics
Volume44
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

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Protein-Tyrosine Kinases
Lung Neoplasms
Phosphotransferases
Neoplasms
Mutation
Epithelial-Mesenchymal Transition
Non-Small Cell Lung Carcinoma
Up-Regulation
Therapeutics
Pharmacology
Ligands
Erlotinib Hydrochloride
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics

Cite this

Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., Laframboise, T., ... Bivona, T. G. (2012). Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics, 44(8), 852-860. https://doi.org/10.1038/ng.2330

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. / Zhang, Zhenfeng; Lee, Jae Cheol; Lin, Luping; Olivas, Victor; Au, Valerie; Laframboise, Thomas; Abdel-Rahman, Mohamed; Wang, Xiaoqi; Levine, Alan D.; Rho, Jin Kyung; Choi, Yun Jung; Choi, Chang Min; Kim, Sang We; Jang, Se Jin; Park, Young Soo; Kim, Woo Sung; Lee, Dae Ho; Lee, Jung Shin; Miller, Vincent A.; Arcila, Maria; Ladanyi, Marc; Moonsamy, Philicia; Sawyers, Charles; Boggon, Titus J.; Ma, Patrick C.; Costa, Carlota; Taron, Miquel; Rosell, Rafael; Halmos, Balazs; Bivona, Trever G.

In: Nature Genetics, Vol. 44, No. 8, 08.2012, p. 852-860.

Research output: Contribution to journalArticle

Zhang, Z, Lee, JC, Lin, L, Olivas, V, Au, V, Laframboise, T, Abdel-Rahman, M, Wang, X, Levine, AD, Rho, JK, Choi, YJ, Choi, CM, Kim, SW, Jang, SJ, Park, YS, Kim, WS, Lee, DH, Lee, JS, Miller, VA, Arcila, M, Ladanyi, M, Moonsamy, P, Sawyers, C, Boggon, TJ, Ma, PC, Costa, C, Taron, M, Rosell, R, Halmos, B & Bivona, TG 2012, 'Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer', Nature Genetics, vol. 44, no. 8, pp. 852-860. https://doi.org/10.1038/ng.2330
Zhang Z, Lee JC, Lin L, Olivas V, Au V, Laframboise T et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics. 2012 Aug;44(8):852-860. https://doi.org/10.1038/ng.2330
Zhang, Zhenfeng ; Lee, Jae Cheol ; Lin, Luping ; Olivas, Victor ; Au, Valerie ; Laframboise, Thomas ; Abdel-Rahman, Mohamed ; Wang, Xiaoqi ; Levine, Alan D. ; Rho, Jin Kyung ; Choi, Yun Jung ; Choi, Chang Min ; Kim, Sang We ; Jang, Se Jin ; Park, Young Soo ; Kim, Woo Sung ; Lee, Dae Ho ; Lee, Jung Shin ; Miller, Vincent A. ; Arcila, Maria ; Ladanyi, Marc ; Moonsamy, Philicia ; Sawyers, Charles ; Boggon, Titus J. ; Ma, Patrick C. ; Costa, Carlota ; Taron, Miquel ; Rosell, Rafael ; Halmos, Balazs ; Bivona, Trever G. / Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. In: Nature Genetics. 2012 ; Vol. 44, No. 8. pp. 852-860.
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