Abstract IA05: Next-generation strategies to target RAF

Abstract

Abstract RAF is a well-studied effector of RAS. Oncogenic activation of BRAF fuels cancer growth by constitutively promoting MAPK pathway signaling independent of RAS activation. Efforts to develop agents to block mutated BRAF have brought substantial therapeutic improvement in personalized treatment of metastatic melanoma. Nonetheless, many patients relapse and relapsed tumors generally display MAPK pathway re-activation. The development of these agents also revealed an unexpected consequence of these targeted therapies: stimulated growth of certain cancers. Structurally-diverse ATP-competitive RAF kinase inhibitors can either inhibit or paradoxically activate the MAPK pathway depending whether the pathway is activated by a BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. We have identified next generation RAF inhibitors (dubbed “paradox breakers”) that inhibit mutant RAF cells without activating the MAPK pathway in cells containing an upstream activation event. These new inhibitors maintain efficacy in BRAF-driven cell and animal models. In a cell model that expresses the same HRAS mutation prevalent in squamous cell tumors from patients treated with RAF inhibitors, first-generation RAF inhibitors stimulate the in vitro and in vivo growth of the cells and induce the expression of MAPK pathway response genes including EGFR ligands; by contrast paradox breakers such as PLX8394 had no effect. In addition, PLX8394 is able to overcome several known mechanisms of resistance to first generation RAF inhibitors. By dissociating MAPK pathway inhibition from pathway activation, the next generation RAF inhibitors may yield both improved safety and more durable efficacy than first generation RAF inhibitors. Citation Format: Gideon Bollag. Next-generation strategies to target RAF. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA05. doi: 10.1158/1557-3125.RASONC14-IA05