Abstract 4422: A Hippo-independent pathway modulates YAP-induced resistance of cancer cells to antitubulin drugs

Abstract

Abstract Antitubulin drugs have been widely used for the treatment of various human cancers including breast and lung cancer, etc. Although these drugs are effective as first-line treatment of cancers, many cancer patients are either intrinsically resistant or later develop resistant to drugs, which is one of the major obstacles for successful cancer treatment. Therefore, understanding the molecular mechanism underlying antitubulin drug resistance is critical for future prognosis of cancer treatment and development of novel therapeutic drugs for cancer treatment. The Hippo pathway is an emerging signaling pathway that plays important roles in various biological processes including organ size control, tumorigenesis, stem cell differentiation and renewal, etc. Although tremendous progress has been made toward our understanding of the roles of the Hippo pathway in cancer development, if and how is its role in drug resistance remains largely unknown. Recently, we and others have provided convincing evidence that some core components of the Hippo pathway are involved in the resistance of cancer cells to antitubulin drug Taxol. However, the signaling pathways or genes mediating their effects in chemotherapeutic drug response remain to be identified. In this study, we have discovered that Hippo core component YAP oncoprotein and transcriptional co-activitor is specifically phosphorylated only after treatment of cancer cells with antitubulin drugs. Most significantly, we have identified a Hippo-independent pathway in which activated Cdk1 can directly phosphorylate YAP, which subsequently inactivates YAP function in transactivation and anti-apoptosis during antitubulin drug treatment. These findings have significant implication not only in future use of YAP as a prognostic marker in predicting antitubulin drug response in patients but also provide a novel approach for future targeting and inactivating YAP by activating its phosphorylation for treatment of antitublin drug resistant cancer patients caused by YAP activation. Citation Format: Yulei Zhao, Prem Khanal, Xiaolong Yang. A Hippo-independent pathway modulates YAP-induced resistance of cancer cells to antitubulin drugs. [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 4422. doi:10.1158/1538-7445.AM2014-4422