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

被引：985

作者：

Zhang, Zhenfeng ^{[2
,3
,5
]}

Lee, Jae Cheol ^{[6
]}

Lin, Luping ^{[1
]}

Olivas, Victor ^{[1
]}

Au, Valerie ^{[5
]}

LaFramboise, Thomas ^{[3
,7
]}

Abdel-Rahman, Mohamed ^{[3
,4
]}

Wang, Xiaoqi ^{[5
]}

Levine, Alan D. ^{[2
,3
,8
]}

Rho, Jin Kyung ^{[9
]}

Choi, Yun Jung ^{[9
]}

Choi, Chang-Min ^{[6
,9
]}

Kim, Sang-We ^{[6
]}

Jang, Se Jin ^{[10
]}

Park, Young Soo ^{[10
]}

Kim, Woo Sung ^{[9
]}

Lee, Dae Ho ^{[6
]}

Lee, Jung-Shin ^{[6
]}

Miller, Vincent A.

Arcila, Maria ^{[11
]}

Ladanyi, Marc ^{[11
,12
]}

Moonsamy, Philicia ^{[12
]}

Sawyers, Charles ^{[12
]}

Boggon, Titus J. ^{[13
]}

Ma, Patrick C. ^{[14
,15
]}

Costa, Carlota ^{[16
,17
]}

Taron, Miquel ^{[16
,17
]}

Rosell, Rafael ^{[16
,17
]}

Halmos, Balazs ^{[5
]}

Bivona, Trever G. ^{[1
,12
]}

机构：

[1] Univ Calif San Francisco, Div Hematol Oncol, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA

[2] Case Western Reserve Univ, Sch Med, Dept Pathol, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA

[3] Case Comprehens Canc Ctr, Ireland Canc Ctr, Cleveland, OH USA

[4] Case Western Reserve Univ, Sch Med, Div Hematol Oncol, Univ Hosp Case Med Ctr, Cleveland, OH USA

[5] Columbia Univ, Div Hematol Oncol, Med Ctr, New York, NY USA

[6] Univ Ulsan, Dept Oncol, Asan Med Ctr, Coll Med, Seoul, South Korea

[7] Case Western Reserve Univ, Sch Med, Dept Genet, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA

[8] Case Western Reserve Univ, Sch Med, Div Gastroenterol & Liver Dis, Univ Hosp Case Med Ctr, Cleveland, OH USA

[9] Univ Ulsan, Asan Med Ctr, Coll Med, Dept Pulm & Crit Care Med, Seoul, South Korea

[10] Univ Ulsan, Asan Med Ctr, Coll Med, Dept Pathol, Seoul, South Korea

[11] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[12] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[13] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

[14] Case Western Reserve Univ, Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA

[15] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA

[16] Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Barcelona, Spain

[17] USP Dexeus Univ Inst, Pangaea Biotech, Barcelona, Spain

来源：

NATURE GENETICS | 2012年 / 44卷 / 08期

基金：

美国国家卫生研究院;

关键词：

RECEPTOR TYROSINE KINASES; NF-KAPPA-B; ACQUIRED-RESISTANCE; MET AMPLIFICATION; MUTANT EGFR; GEFITINIB; MUTATIONS; TUMORS; ERLOTINIB; GROWTH;

D O I：

10.1038/ng.2330

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFRtargeted 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.

引用

页码：852 / +

页数：11

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