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.
authors: 1] Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals-Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: Zhenfeng
authors: Z
authors: Zhang
authors: Jae Cheol
authors: JC
authors: Lee
authors: Luping
authors: L
authors: Lin
authors: Victor
authors: V
authors: Olivas
authors: Valerie
authors: V
authors: Au
authors: Thomas
authors: T
authors: LaFramboise
authors: Mohamed
authors: M
authors: Abdel-Rahman
authors: Xiaoqi
authors: X
authors: Wang
authors: Alan D
authors: AD
authors: Levine
authors: Jin Kyung
authors: JK
authors: Rho
authors: Yun Jung
authors: YJ
authors: Choi
authors: Chang-Min
authors: CM
authors: Choi
authors: Sang-We
authors: SW
authors: Kim
authors: Se Jin
authors: SJ
authors: Jang
authors: Young Soo
authors: YS
authors: Park
authors: Woo Sung
authors: WS
authors: Kim
authors: Dae Ho
authors: DH
authors: Lee
authors: Jung-Shin
authors: JS
authors: Lee
authors: Vincent A
authors: VA
authors: Miller
authors: Maria
authors: M
authors: Arcila
authors: Marc
authors: M
authors: Ladanyi
authors: Philicia
authors: P
authors: Moonsamy
authors: Charles
authors: C
authors: Sawyers
authors: Titus J
authors: TJ
authors: Boggon
authors: Patrick C
authors: PC
authors: Ma
authors: Carlota
authors: C
authors: Costa
authors: Miquel
authors: M
authors: Taron
authors: Rafael
authors: R
authors: Rosell
authors: Balazs
authors: B
authors: Halmos
authors: Trever G
authors: TG
authors: Bivona
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C512478:EGFR protein, human; C491743:MET protein, human; C000722289:AXL protein, human