Abstract 2428: Molecular determinants of dasatinib response in uterine carcinoma.

Abstract

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Despite the many attractive features of EphA2 as a therapeutic target in cancer, approaches to block it have lagged behind. Dasatinib is a multi-kinase inhibitor and may be useful for targeting EphA2. However, reliable predictive markers of response are needed. Additionally, the underlying mechanism deciding whether responsive or resistant to dasatinib and biological impact of EphA2 function in the context of EphA2 targeted therapy in cancer are not known.

We undertook a large number of studies to fully characterize the effects of dasatinib using in vitro (cell viability, RPPAs, gene expression, and confocal imaging) and in vivo uterine cancer models. Molecular markers for response prediction were identified by using RPPA and immunohistochemistry.

In vitro, the effects of dasatinib treatment varied among the different endometrial cancer cell lines tested, (IC50 values ranged from 30 nM to 17,792 nM), which was associated with varying levels of EphA2 and tyrosine phosphorylation and serine897 phosphorylation of EphA2, and with varying status of caveolin-1 (CAV-1), PTEN and RAS/MAPK . A set of markers that are essential for dasatinib response was identified, including EphA2, CAV-1, pAKTs473, BRAF/CRAF (MAPK pathway) and ppS6s240/244 (mTOR pathway). A novel mechanism for response was identified by which dasatinib can drive the BRAF and EphA2 to CAV-1 at the plasma membrane, resulting in breaking off the BRAF/CRAF heterodimer induced by dasatinib, and blocking compensatory activation of the MAPK pathway. In vivo data using orthotopic mouse models of uterine carcinoma were entirely concordant with our in vitro findings.

The efficacy of dasatinib therapy in uterine carcinoma depends on EphA2 phosphorylation at its S897 site and high CAV-1 levels are predictive of response to dasatinib. These findings may have clinical implications for ongoing dasatinib-based clinical trials.

Citation Format: Jie Huang, Wei Hu, Justin Bottsford-Miller, Tao Liu, Behrouz Zand, Robert L. Coleman, Anil K. Sood. Molecular determinants of dasatinib response in uterine carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2428. doi:10.1158/1538-7445.AM2013-2428