Abstract 934: MEK162, an allosteric MEK inhibitor promotes apoptosis and in vivo antitumor activity against human biliary cancer cell lines.

Abstract

Abstract Biliary cancer (BC), or cholangiocarcinoma, is derived from the malignant transformation of epithelial cells in the bile ducts. The disease usually presents at advanced stages and is almost uniformly deadly. Current therapeutic regimens have limited efficacy for treatment of BC, thus the need for developing novel and effective targeted strategies is a priority. This malignancy is characterized by deregulated PI3 kinase/Akt signaling, upregulated mitogen-activated protein kinase (MAPK) pathway and an autocrine IL-6/STAT3 signal transduction feedback loop, which can also drive immunosuppression. A recent report showed clinical responses for BC patients receiving the MEK inhibitor AZD244, which promoted more extensive pre-clinical studies to validate the effect of MEK inhibition and importance of this pathway in BC. In the present study, MEK162, a MEK inhibitor, was used to assess the growth inhibitory, pro-apoptotic, and immunomodulatory effects in BC. In vitro studies in a panel of human BC cell lines (HuCCT1, HuH28, MzCha1) revealed that MEK162 significantly inhibited cell growth and induced apoptosis in a concentration-dependent manner in all three cell lines. Immunoblot data confirmed decreased phosphorylated ERK (pERK) in the HuCCT1 BC cell line following a 24 hour treatment with MEK162. MEK inhibition was also associated with clinically-relevant immunomodulatory effects. First, culture supernatants from human BC cells displayed significant reductions in IL-6 protein by ELISA after treatment with MEK162 at varying concentrations. Second, MEK162 inhibited in vitro generation of human myeloid derived suppressor cells from peripheral blood mononuclear cells cultured with IL-6 and GM-CSF. Finally, in vivo studies in athymic mice bearing HuCCT1 xenografts showed that daily oral administration of MEK162 (30 mg/kg in 1% (w/v) carboxymethylcellulose, 0.5% (v/v) Tween 80) was well-tolerated and resulted in significant growth inhibition as compared to vehicle-treated controls (p < 0.0001). Immunohistochemical analysis of tumor xenografts revealed significant decreases in both Ki67 and pERK staining in the MEK162-treated mice as compared to controls (p = 0.0163 and 0.0132,respectively). Together, these data suggest that MEK inhibition represents a promising therapeutic approach with potential for direct antitumor activity and immunomodulation in BC. Citation Format: Jennifer Yang, Thomas A. Mace, Gergory S. Young, Patrice A. Lee, Kaitlin E. Keenan, Zheng Che, Tonios Bekaii-saab, Gregory B. Lesinski. MEK162, an allosteric MEK inhibitor promotes apoptosis and in vivo antitumor activity against human biliary cancer cell lines. [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 934. doi:10.1158/1538-7445.AM2013-934