Abstract 2621: Characterizing MEK1/2 degradation in K-ras mutant cells

Abstract

Abstract Activating KRAS mutations frequently occur in several cancers including the majority of pancreatic ductal adenocarcinoma (96%), ~50% of colorectal cancers, and ~30% of lung adenocarcinoma. It has been shown that mutant K-ras preferentially signals through RAF-MEK-ERK signaling and that blockade of this pathway is essential for tumor regression. However, targeted MEK inhibitors (MEKi) have shown limited clinical benefit in the treatment of K-ras mutant cancers due to resistance caused by the feedback activation of the upstream kinase CRAF. Recently, PROTACs (Proteolysis-Targeting Chimeras) targeting MEK1 and MEK2 were developed, providing a new therapeutic strategy to degrade MEK1/2 in K-ras mutant cancer cells. Due to the fact that feedback-induced CRAF causes MEKi resistance in K-ras mutant cells, we postulated that degrading MEK1/2 could bypass CRAF-mediated resistance. Indeed, treatment of MEKi-sensitive or resistant K-ras mutant cell lines with MEK1/2 degraders rapidly reduced MEK1/2 protein levels and downstream ERK signaling causing growth inhibition and apoptosis. Proteomics characterization of K-ras mutant cell lines following MEK1/2 degrader or inhibitor treatment revealed MEK1/2 degradation exhibited distinct signaling pathway responses compared to inhibition. Together, our studies showed MEK1/2 degraders represent a promising avenue for the treatment K-ras mutant cancers that can by-pass resistance mechanisms observed with traditional MEK1/2 inhibitors. Citation Format: Carlos Herrera-Montavez, Alison M. Kurimchak, Jian Jin, James S. Duncan. Characterizing MEK1/2 degradation in K-ras mutant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2621.