Epigenetic Targeting Of Survivin Enhances Paclitaxel-Mediated Antitumor Activity Against Non-Small-Cell Lung Cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Lung cancer is the leading cause of cancer-related deaths worldwide and has a low 5-year survival rate. The current treatment for lung cancer patients is surgical resection followed by chemotherapy. However, the majority of patients will eventually experience disease progression and require further treatment. Increased evidence indicates that overexpression of survivin, the smallest member of IAP (inhibitor of apoptosis) family, results in poor prognosis, tumor recurrence, and drug resistance in various cancers, including non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases. Although the precise mechanism leading to survivin overexpression in cancer cells is not fully understood, approach to effectively downregulate survivin is thought to be required to enhance chemotherapy, reduce relapse, and improve the survival of NSCLC patients. In the present study, we have explored the therapeutic potential of the class I HDAC inhibitor (HDACi) entinostat (or MS-275, SNDX-275, LC Laboratories, Woburn, MA) in combination with paclitaxel in the treatment of NSCLC. We show that entinostat significantly enhances paclitaxel-induced anti-proliferative/anti-survival effects and apoptosis in NSCLC cells. It appears that this HDACi selectively reduces the expression levels of survivin, but not the functionally-related molecules Mcl-1 and Bcl-xL. Further studies reveal that entinostat induces expression of two survivin-targeting miRNAs, miR-203 and miR-542-3p; and that both survivin-specific shRNAs and the mimics of miR-203 and/or miR-542-3p effectively downregulate survivin and dramatically promote NSCLC cells undergoing apoptosis upon paclitaxel treatment. Moreover, in a tumor xenografts model-established from NSCLC cells, entinostat maintains its capability to upregulate miR-203 and downregulate survivin in vivo. Importantly, the combinations of entinostat and paclitaxel exhibit a striking activity, as compared to either agent alone, to inhibit tumor growth. These data indicate that entinostat is efficacious to enhance paclitaxel-mediated anti-NSCLC activity. Our findings suggest that epigenetic targeting of survivin with entinostat or miRNA-replacement therapy may be a novel strategy to re-sensitize NSCLC to chemotherapy. Numerous studies demonstrate that entinostat exerts potent antitumor activity in various human cancers. Its clinic activity in NSCLC is currently being tested in combination with the DNA methyltransferase inhibitor Azacitidine or EGFR inhibitor erlotinib, but not conventional chemotherapy ( = entinostat&Search = Search). Our studies provide a strong rationale to initiate clinical evaluation of the combinatorial effects of entinostat and paclitaxel on NSCLC patients. Citation Format: Shuiliang Wang, Ling Zhu, Zhiyong Zeng, Lianghu Huang, Fengjin Lin, Rong Lin, Jin Wang, Jun Lu, Qinghua Wang, Lingjing Lin, Huiyue Dong, Weizhen Wu, Kai Zheng, Jinquan Cai, Shunliang Yang, Yujie Ma, Shixin Ye, Wei Liu, Yinghao Yu, Bolin Liu, Jianming Tan. Epigenetic targeting of survivin enhances paclitaxel-mediated antitumor activity against non-small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5382. doi:10.1158/1538-7445.AM2015-5382