Abstract 3755: Restoring sensitivity to cisplatin or TRAIL by targeting drug resistance master regulators in endometrial cancer

Abstract

Abstract Understanding the molecular mechanisms of drug resistance is vital to enhance the efficacy of current therapeutic regimens. In particular, metadherin (MTDH) and FOXM1 overexpression has been independently demonstrated to have a critical role in chemoresistance. Overexpression of MTDH correlates with poor clinical outcome in many cancers, including endometrial cancer. Our previous study showed that endometrial cancer cells are sensitive to the combination treatment of tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) with histone deacetylase (HDAC) inhibitor LBH589, an effect that could be enhanced by depletion of MTDH. In this study, we focused on the therapeutic strategies to restore sensitivity to chemotherapeutic agent cisplatin or apoptosis-inducing TRAIL by disrupting drug resistance genes FOXM1 or MTDH. CUDC907 is a novel investigational dual inhibitor designed to target PI3K and HDACs. The high frequency of PI3K /PTEN/AKT pathway dysregulation in endometrial cancer suggests that CUDC907 will also be effective in this disease. Indeed, CUDC907 potently induced apoptosis when combined with TRAIL in MTDH-depleted endometrial cancer cells. Cisplatin is a frontline treatment for advanced endometrial cancers. However, drug resistance causes treatment failure. Although the detailed mechanisms of drug resistance are still elusive, gradual induction of FOXM1 and its downstream target gene network may be involved in the development of resistance to cisplatin. We found that co-treatment with cisplatin and the Nedd8 conjugation system inhibitor MLN4924 restored sensitivity to cisplatin by down-regulating drug resistant gene FOXM1. These findings imply that simultaneously depleting drug resistant master genes, such as MTDH and FOXM1, is a potentially novel avenue for reversing therapeutic resistance to current chemotherapy and targeted therapies in patients with endometrial cancer. Citation Format: Xiangbing Meng, Shujie Yang, Xinjun Wang, Yichen Jia, Yuping Zhang, Kimberly K. Leslie. Restoring sensitivity to cisplatin or TRAIL by targeting drug resistance master regulators in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3755. doi:10.1158/1538-7445.AM2014-3755