Abstract 860: The multi-targeted kinase inhibitor Sunitinib induces apoptosis in colon cancer cells via PUMA

Abstract

Abstract Key words: Sunitinib; PUMA; FoxO3a; Bcl-2 family; colon cancer Purpose: Sunitinib is a FDA approved multi-targeted receptor tyrosine kinase (RTK) inhibitor for treating solid tumors. Inhibition of angiogenesis, immune modulation and induction of apoptosis has been suggested to mediate the anti-tumor effects of sunitinib. However, its cell killing mechanisms are not well-understood. In this study, we investigated the mechanisms and significance of sunitinib-mediated apoptosis in its antitumor activities using colon cancer cells and xenografts. Experimental Design: The expression of various Bcl-2 family proteins, apoptosis and long-term growth in response to sunitinib were examined in colon cancer cells. The mechanism of PUMA induction and effects of PUMA deficiency, BH3 mimetics and 5-FU on sunitinib-induced apoptosis were investigated. The effects of PUMA deficiency in responses to sunitinib were determined in xenografts. Results: We found that consistent PUMA induction mediated by transcription factor FoxO3a plays an important role in the apoptosis induced by sunitinib. PUMA deficiency led to impaired apoptosis and caspase activation in colon cancer cells with either wildtype or mutant p53. Small molecule BH3 mimetics or elevated PUMA levels sensitized colon cancer cells to sunitinib-induced apoptosis. PUMA deficiency significantly blocked apoptosis and therapeutic responses to sunitinib in xenografts. Conclusions: Our results establish a critical role of PUMA in mediating sunitinib sensitivity in colon cancer cells and lack of apoptosis induction as a potential resistance mechanism. Our study suggests modulations of Bcl-2 family proteins as potential biomarkers, and combination of sunitinib with BH3 mimetics or chemotherapeutic agents might improve the treatment efficacy in colon cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 860. doi:1538-7445.AM2012-860