Abstract 4568: Rapid assessment of TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF mutant melanoma.

Abstract

Abstract The clinical development and potent efficacy of selective RAF and MEK inhibitors has transformed the treatment of the ∼50% of melanoma patients whose tumors harbor BRAF mutations. However, a substantial percentage of these patients fail to respond to therapy, and all who respond eventually develop resistance. We found that suppression of TORC1 activity, as measured by decreases in ribosomal protein S6 phosphorylation (P-S6) in response to RAF or MEK inhibitors, was a highly effective predictor of sensitivity in BRAF mutant melanoma cell lines in vitro and in mouse xenografts. TORC1 and P-S6 were suppressed in response to RAF or MEK inhibitors in sensitive but not resistant melanoma cells, despite robust suppression of the MAPK pathway by these inhibitors. Notably, suppression of P-S6 levels, as assessed by immunohistochemistry in paired biopsies obtained from BRAF mutant melanoma patients before and during treatment, was associated with significantly improved progression-free survival. Finally, we show that changes in P-S6 levels specifically in tumor cells can be readily monitored by multiplexed, quantitative immunofluorescence microscopy of fine needle aspiration biopsies obtained from patients before and during the first two weeks of BRAF inhibitor therapy. This provides a minimally invasive means for monitoring the efficacy of treatment in real time, before changes in tumor volume are apparent on traditional radiographs. Together, these results establish changes in P-S6 levels with therapy as a robust biomarker to guide the treatment of patients with BRAF mutant melanoma, and present a powerful methodology for monitoring changes in potentially any signaling pathway in response to therapy in patients. Citation Format: Ryan B. Corcoran, Stephen M. Rothenberg, Aaron N. Hata, Anthony C. Faber, Daniel Winokur, Adriano Piris, Rosalynn M. Nazarian, Ronald D. Brown, Jason T. Godfrey, Mari Mino-Kenudson, Jeffrey Settleman, Jennifer A. Wargo, Keith T. Flaherty, Daniel A. Haber, Jeffrey A. Engelman. Rapid assessment of TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF mutant melanoma. [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 4568. doi:10.1158/1538-7445.AM2013-4568