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: 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
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 8 Pg. 852-60 (Jul 01 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22751098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Quinazolines
• growth arrest-specific protein 6
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Adult
• Aged
• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation
• Epithelial-Mesenchymal Transition
• ErbB Receptors (antagonists & inhibitors, genetics)
• Erlotinib Hydrochloride
• Female
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Quinazolines (pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays
• Axl Receptor Tyrosine Kinase