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; Marc Ladanyi; Philicia Moonsamy; Charles Sawyers; Titus J. Boggon; Patrick C. Ma; Carlota Costa; Miquel Taron; Rafael Rosell; Balazs Halmos; Trever G. Bivona

doi:10.1038/ng.2330

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 ArcilaMarc 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 journal › Article › peer-review

985 Scopus citations

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 language	English (US)
Pages (from-to)	852-860
Number of pages	9
Journal	Nature Genetics
Volume	44
Issue number	8
DOIs	https://doi.org/10.1038/ng.2330
State	Published - Aug 2012
Externally published	Yes

ASJC Scopus subject areas

Genetics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2330

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Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., Laframboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., Choi, Y. J., Choi, C. M., Kim, S. W., Jang, S. J., Park, Y. S., Kim, W. S., Lee, D. H., Lee, J. S., Miller, V. A., ... 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

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

@article{19371ab945954d25bc02b6d778b7f6f2,

title = "Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer",

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.",

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

note = "Funding Information: The authors thank K. Shokat for assistance with structural modeling of the AXL gatekeeper mutation, W. Polkinghorn, J. Wongvipat and E. Chan for advice and technical assistance and S. Edelheit of the Case Genomics Center for technical assistance. This work was supported by the Korean Health Technology R&D Project (grant A102059 to J.C.L.), the US National Institutes of Health (K08 1K08CA154787 to T.G.B. and P01 CA129243 to M.L.), a Uniting Against Lung Cancer Research Award, a National Lung Cancer Partnership Young Investigator Award (to T.G.B.), a grant from the La Caixa Foundation (to R.R.) and an American Cancer Society Research Scholar Grant (RSG-08-303-01 to B.H.).",

year = "2012",

month = aug,

doi = "10.1038/ng.2330",

language = "English (US)",

volume = "44",

pages = "852--860",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

AU - Zhang, Zhenfeng

AU - Lee, Jae Cheol

AU - Lin, Luping

AU - Olivas, Victor

AU - Au, Valerie

AU - Laframboise, Thomas

AU - Abdel-Rahman, Mohamed

AU - Wang, Xiaoqi

AU - Levine, Alan D.

AU - Rho, Jin Kyung

AU - Choi, Yun Jung

AU - Choi, Chang Min

AU - Kim, Sang We

AU - Jang, Se Jin

AU - Park, Young Soo

AU - Kim, Woo Sung

AU - Lee, Dae Ho

AU - Lee, Jung Shin

AU - Miller, Vincent A.

AU - Arcila, Maria

AU - Ladanyi, Marc

AU - Moonsamy, Philicia

AU - Sawyers, Charles

AU - Boggon, Titus J.

AU - Ma, Patrick C.

AU - Costa, Carlota

AU - Taron, Miquel

AU - Rosell, Rafael

AU - Halmos, Balazs

AU - Bivona, Trever G.

N1 - Funding Information: The authors thank K. Shokat for assistance with structural modeling of the AXL gatekeeper mutation, W. Polkinghorn, J. Wongvipat and E. Chan for advice and technical assistance and S. Edelheit of the Case Genomics Center for technical assistance. This work was supported by the Korean Health Technology R&D Project (grant A102059 to J.C.L.), the US National Institutes of Health (K08 1K08CA154787 to T.G.B. and P01 CA129243 to M.L.), a Uniting Against Lung Cancer Research Award, a National Lung Cancer Partnership Young Investigator Award (to T.G.B.), a grant from the La Caixa Foundation (to R.R.) and an American Cancer Society Research Scholar Grant (RSG-08-303-01 to B.H.).

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

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

Abstract

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