Abstract
The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration in vitro and exerted significant antitumor activity in vivo. AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.
Highlights
AXL, a member of the mammalian TYRO3, AXL, and MER (TAM) receptor kinase family, is a cellsurface transmembrane receptor that exerts regulated kinase activity through its cytoplasmic domain
We evaluated the effect of DS-1205b, a novel, specific, small-molecule inhibitor of AXL kinase, on tumor growth and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
We examined the effects of combined treatment with erlotinib or osimertinib and DS-1205b on EGFR and AXL downstream signaling with the aim to elucidate the mechanism of action of the compounds, using a cellbased assay
Summary
AXL, a member of the mammalian TYRO3, AXL, and MER (TAM) receptor kinase family, is a cellsurface transmembrane receptor that exerts regulated kinase activity through its cytoplasmic domain. It plays important roles in migration, invasion, cell cycle, and drug sensitivity in malignant cells [1,2,3]. GAS6 is the major ligand for TAM receptor tyrosine www.oncotarget.com kinases and, is the sole ligand for AXL [20]. The binding of GAS6 to its receptors promotes cancer cell proliferation, survival, and migration in vitro [1, 2, 21]
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