Abstract 3725: B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells

Abstract

Abstract B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers such as melanoma and thyroid cancer. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but lead to a paradoxical activation of MEK/ERK signaling in Ras-mutant cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. Given the critical role of MEK/ERK signaling in the positive regulation of DR5 expression as we have previously demonstrated, this study focuses on determining the impact of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-treatment of Ras-mutated cancer cells with PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells. Our results may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition. (This study was supported by Emory Winship Cancer Institute Robbins Scholar awards to YTO and to JD and Halpern Research Scholar award to SYS. SYS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar) Citation Format: You-Take Oh, Jiusheng Deng, Ping Yue, Shi-Yong Sun. B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3725.