Activation of the AXL Kinase Causes Resistance to EGFR-targeted Therapy in Lung Cancer

Overview

Journal Nat Genet

Specialty Genetics

Date 2012 Jul 4

PMID 22751098

Citations 668

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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