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

Abstract

Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non–small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer. 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.