Abstract 337: Degradation of AXL overcome acquired cross-resistance to gefitinib and osimertinib in non-small cell lung cancer cells

Epidermal growth factor receptor (EGFR) mutation is one of the major driver oncogenes in non-small cell lung cancer (NSCLC) and most frequently found in Asian patients. Although the first generation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have led to improved prognoses for NSCLC patients, acquired resistance has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. Recently, AXL has been reported to play a role in drug resistance mechanisms for many anti-cancer drugs, including erlotinib and cetuximab, as well as in ionizing radiation therapy for multiple cancers. In the present study, we demonstrate the involvement of AXL in the acquired resistance to gefitinib and osimertinib of EGFR-mutant NSCLC cells, then show the combination effect of an AXL degrader and EGFR-TKIs to overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells. We found that AXL was overexpressed and its degradation was delayed in EGFR-TKI-resistant NSCLC cells. Yuanhuadine (YD), a natural antitumor agent, effectively suppressed the expression of AXL by accelerating protein degradation. YD combined with gefitinib or osimertinib synergistically inhibited the growth of resistant cells in vitro and suppressed tumor growth in a nude mouse xenograft model. Moreover, administration of YD with gefitinib effectively delayed gefitinib-driven acquired resistance in a long-term xenograft model. Our results suggest that the combination of YD with either gefitinib or osimertinib is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC by targeting AXL degradation. Citation Format: Donghwa Kim, Duc-Hiep Bach, Yan-hua Fan, Thi-Thu-Trang Luu, Ji-Young Hong, Hyen-Joo Park, Sang Kook Lee. Degradation of AXL overcome acquired cross-resistance to gefitinib and osimertinib in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 337.