KRAS was one of the earliest identified oncogenes, and is commonly mutated in pancreatic, lung, and colorectal cancer. Despite strenuous effort, KRAS remained “undruggable” for decades following its discovery until the relatively recent development and approval of drugs which target the KRAS G12C mutation. While these compounds represent a major breakthrough for the field, they are not curative in clinical practice, and the transient nature of responses to KRAS inhibitors indicates the need for additional investigations to achieve durable responses. Here, co-principal investigators Jedd Wolchok and Taha Merghoub will explore combinatorial approaches using immunotherapeutic agents to maximize the therapeutic benefit of KRAS-targeting drugs and advance patient outcomes. This project aims to investigate the integration of novel RAS inhibitors with immune-based therapies to enhance therapeutic efficacy in KRAS mutant cancers.
The experimental plan funded by this ASPIRE award will first focus on defining optimal treatment regimens for RAS inhibitors in syngeneic mouse models by testing different classes of molecules that target specific mutations. The goal is to determine the direct and indirect effects of these inhibitors on the immune system and tumor microenvironment while achieving tumor growth inhibition and optimal immune activation. Combinations of KRAS inhibitors and immune modulatory agents, such as immune checkpoint inhibitors, will then be explored to assess their efficacy compared to single-agent activity. Finally, the investigators will evaluate the impact of KRAS inhibition on the human lung cancer microenvironment by analyzing patient tumor samples treated with KRAS inhibitors. By investigating the effects of RAS inhibitors on immune cells, tumor antigen presentation, and the tumor immune microenvironment, the project aims to design treatment regimens that maximize immune cell stimulation while minimizing toxicity. The integration of targeted therapies with immunotherapies could lead to improved efficacy by inducing tumor cell death and broadening the anti-tumor immune response.