LAUSR

The RAS pathway is one of the most commonly deregulated pathways in human cancer. Approximately 30% of all tumors harbor activating mutations in either KRAS, NRAS or HRAS, and even more possess alterations in other genes that enhance RAS signaling. While RAS was thought to be undruggable for decades, agents that directly inhibit KRAS and/or specific KRAS oncoproteins have now been developed. Nevertheless, not all patients respond to current clinical agents and responses are often temporary. As such there is an urgent need to develop more effective therapies for these malignancies, which will likely require combinatorial approaches. Vertical strategies designed to target different nodes within the RAS pathway to achieve deeper suppression represents one promising approach. However, additional options are emerging, which may circumvent challenges associated with potent pathway suppression. In this presentation, two promising combinatorial strategies for KRAS mutant lung and colon cancer will be discussed. Importantly, by dissecting the mechanism by which these agents function we have uncovered nodal points of convergence between distinct oncogenic pathways, which represent key therapeutic vulnerabilities, and have identified biomarkers that can be used for patient selection. Citation Format: Karen Cichowski. Developing combinatorial therapies for KRAS-driven cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA12.