PURPOSE: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EGFR
EXPERIMENTAL DESIGN: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in-mutated NSCLC cells usingandexperiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. EGFR in vitro in vivo EGFR
RESULTS: ONO-7475 sensitized AXL-overexpressing-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. EGFR EGFR
CONCLUSIONS: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment. EGFR
