Journal
NATURE GENETICS
Volume 44, Issue 8, Pages 852-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2330
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Funding
- Korean Health Technology RD Project [A102059]
- US National Institutes of Health [K08 1K08CA154787, P01 CA129243]
- Uniting Against Lung Cancer Research Award
- National Lung Cancer Partnership Young Investigator Award
- La Caixa Foundation
- American Cancer Society Research Scholar Grant [RSG-08-303-01]
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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.
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