Abstract 4680: Restoration of EGFR-TKI resistance by endocytosis inhibitor PAO in lung cancer with wild-type EGFR

Abstract

Abstract Therapeutic efficacy of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is currently limited in selected lung cancer patients who have TKI sensitive EGFR mutation. However, the potential molecular mechanism that expands the therapeutic benefit of EGFT-TKI in patients who have wild-type EGFR non-small cell lung cancer (wtEGFR NSCLC) remains unclear. Recently, several studies revealed EGFR endocytosis mechanism could mediate signal transductions that influence in cancer cell proliferation. Moreover, our previous study demonstrated that EGFR endocytosis is related to gefitinib sensitivity in wtEGFR NSCLC and EGFR endocytosis could be a novel therapeutic target in lung cancer with wtEGFR (Oncotarget. 2014 15;5(5):1265-78). In this study, we investigated whether EGFR-TKI resistance could be restored in wtEGFR NSCLC cell lines by endocytosis inhibitor phenylarsine oxide (PAO). To investigate effects of PAO in vitro, we analyzed EGF-induced EGFR internalization and performed Annexin V and propodium iodide (PI) staining by flow cytometry. As a result, EGF-induced EGFR endocytosis is decreased and apoptotic cell death is induced accompanied by G0/G1 arrest after PAO treatment. In addition, we observed that cell viability is reduced significantly when PAO and EGFR-TKIs (gefitinib, erlotinib) treated together. Furthermore, we verified signaling transduction that associated with proliferation and apoptosis by western blot. To confirm combination effects of PAO and EGFR-TKI in vivo, we established xenograft mouse model using gefitinib-insensitive SNU1327 cell lines. After Tumor sizes reached 100-200mm3, mice were treated with PAO or gefitinib alone, or combined treatment for 3 weeks. We observed that tumor sizes of combination group were more decreased than other groups.In these result, we validate endocytosis inhibitor PAO is potential drug for overcoming therapeutic limitation of EGFR-TKI in gefitinib-insensitive wtEGFR NSCLC cell lines, though further experiment is needed to explain more accurate mechanism. This study was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2057538). Citation Format: Boyeon Kim, Jae Sook Sung, Yeul Hong Kim. Restoration of EGFR-TKI resistance by endocytosis inhibitor PAO in lung cancer with wild-type EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4680.