Abstract 1267: A novel mitochondria-based targeting to restore therapeutic responsiveness in cisplatin- and geftinib-resistant human lung cancer cells

BACKGROUND: Cisplatin and tyrosine kinase inhibitors (TKIs) are recommended to treat non-small-cell lung cancer (NSCLC). However, ubiquitous acquired drug resistance in NSCLC patients diminishes their therapeutic efficacy. Overcome cisplatin and TKIs resistance is an unmet medical need. DZ-191, a novel synthetic statin derivative, is capable of targeting specifically tumor cells, bypassing the liver. We observed this agent inhibited tumor cell growth in vitro, tumor growth in vivo and accelerated tumor regression in mice. METHODS: Cell viability was examined by crystal violet assay in human NSCLC A549, A549DDP, H1650, and H1975 cells. DZ-191-induced apoptosis in NSCLC cells was detected by Annexin V-FITC/PI staining followed by FACS and confirmed with western blot of apoptosis-associated proteins. Mitochondrial membrane potential was determined by rhodamine-123 followed by flow cytometry. H1650 tumor growth in mice was assessed and autophagy markers were analyzed by western blotting. RESULTS: Treatment with DZ-191 alone inhibited the growth of A549, H1650 and H1975 NSCLC cells, with IC50 values in the range of 8±1μM. In the cisplatin-resistant A549DDP cells, DZ-191 exposure at the IC10, markedly sensitized the cisplatin-resistant A549DDP cells by lowering its IC50 value from 87.6±1.0 to 13.6±1.2 μM. We observed DZ-191, but not statins, significantly increased the apoptosis of A549DDP and H1650 cells. These results are consistent with the observation that DZ191, but not statins, accumulates in mitochondria and lysosomes, resulting in depolarized mitochondrial membrane potential, decreased autophagy and lysosomal protein degradation. We observed decreased autophagy markers, assessed by decreased LC3 conversion and increased p62 accumulation. Combining with our RNA-seq data, DZ191 could induce NSCLC cell death by reducing the removal of damaged mitochondria through mitophagy. Furthermore, we observed DZ-191, but not statins, could resensitize anti-tumor responses of geftinib in a TKI-resistant NSCLC tumor xenografts in nude mice. CONCLUSIONS: These results demonstrated that DZ-191 is superior to statins in inhibiting and resensitizing the anti-tumor responses of cisplatin- and geftinib-resistant NSCLC cells by targeting mitochondria-mediated autophagy and downstream lysosome-related protein degradation. DZ-191 can be employed as a promising sensitizer to overcome cisplatin- and geftinib-resistance in NSCLC patients. Key words: DZ-191, statins, cisplatin- geftinib-resistance, autophagy, NSCLC, mitochondria, lysosomes This work is support in part by US NCI P01 CA098912 and a Board of Governors Chair of Cancer Research fund from Cedars-Sinai Medical Center to LWK Chung and China National 863 Lung Cancer Research Grant (2012AA02A502) and International Technology Targeted Therapeutics Grant (2016YEE0103400) to Q. Zhou Citation Format: Liyuan Yin, Gina Chia-Yi Chu, Ruoxiang Wang, Anisha Madhav, Lijuan Yin, Neil Bhowmick, Haiyen E. Zhau, Qinghua Zhou, Leland W.K. Chung. A novel mitochondria-based targeting to restore therapeutic responsiveness in cisplatin- and geftinib-resistant human 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 1267.