Abstract 894: Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. Epidermal growth factor receptor (EGFR)- targeted tyrosine kinase inhibitors (TKIs), such as gefitinib have improved the survival of NSCLC patients with activating mutations in EGFR. However, the drug responses are only transient because tumors acquire resistance via secondary mutations in EGFR (T790M) or amplification of other receptor tyrosine kinases (RTKs) including MET or AXL. Therefore, the precise mechanisms of chemoresistance and finding the novel ways of targeting cancer cells are needed to be identified. AXL, a TAM (Tyro3, AXL, Mer) family member, has been studied as a tumorigenesis, chemoresistance, and EMT marker. Also, we found that AXL is overexpressed in EGFR mutated gefitinib-resistant non-small lung cancer cells (PC9-gef) compared to its parent cells (PC9). Moreover, the AXL degradation rate was found to be suppressed. These findings suggest that the modulation of AXL turnover can be a therapeutic target to overcome gefitinib-resistance. In this study, we confirmed the possibilities of overcoming gefitinib-resistance through the down-regulation and turnover acceleration of AXL by employing yuanhadine, an anti-tumor agent derived from Daphne Genkwa. Yuanhuadine was also effectively suppressed the tumor growth in nude mouse xenograft models implanted with PC9 or PC9-gef cells. Therefore, regulation of AXL expression by modulating its degradation rate can be a therapeutic strategy to overcome acquired gefitinib-resistance in NSCLC. Citation Format: Donghwa Kim, Duc-Hiep Bach, Ji-Young Hong, Hyen Joo Park, Sang Kook Lee. Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 894.