Abstract 2340: Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action.

Abstract

Abstract KRAS and BRAF mutant cancers represent an area of high unmet medical need in oncology. Multiple allosteric MEK inhibitors are being tested in clinical trials in BRAF mutant and KRAS mutant cancers, where to date they have demonstrated impressive single agent activity in BRAF mutant melanoma, but not in KRAS mutant disease. Active, phosphorylated MEK is elevated in BRAFV600E mutant melanoma tumor models compared to KRAS mutant tumor models, in line with evidence that MAPK pathway regulation differs depending on the upstream oncogenic lesion. However, the precise differences in MEK activation by mutant KRAS or BRAF and how to create MEK inhibitors to block that activation are not known. In this study we describe two clinical, allosteric MEK inhibitors, GDC-0973 and GDC-0623, that have complementary efficacy profiles, with one showing superior efficacy in BRAF mutant models and the other showing superior efficacy in KRAS mutant models. Using structural information and targeted mutagenesis, we demonstrate that although both inhibitors effectively block MEK kinase activity and downstream ERK activation, their unique binding modes result in differential effects on active versus inactive MEK and MEK interaction with RAF that translates into unique efficacy profiles in BRAFV600E versus KRAS mutant tumors. GDC-0973 has already shown promising efficacy as a single agent in BRAFV600E mutant melanoma, and both inhibitors are currently being tested in KRAS mutant tumors in the clinic. Our study highlights that subtle differences in the binding mode of kinase inhibitors can have a large impact on inhibitor/target interactions and efficacy through allosteric mechanisms. These differences may impact the therapeutic index of MEK inhibitors in either BRAF mutant or KRAS mutant cancers. Citation Format: Georgia Hatzivassiliou, Jacob Haling, Huifen Chen, Kyung Song, Shiuh-Ming Luoh, Steve Price, Robert Heald, Mark Zak, Mark Merchant, Klaus Hoeflich, Lori Friedman, Shiva Malek, Marcia P. Belvin. Preferential targeting of KRAS mutant or BRAF mutant tumors using MEK inhibitors with distinct mechanisms of action. [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 2340. doi:10.1158/1538-7445.AM2013-2340