Abstract LB352: KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer

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Abstract RAS mutations are the most common oncogenic mutations, present in >20% of human cancers. KRAS, the predominantly mutated isoform of RAS, is mutated in 40% of colorectal cancer (CRC), leading to constitutive activation of the MAPK (RAS/RAF) pathway and other downstream effectors. Due to the difficulty of targeting RAS, the first KRASG12C selective inhibitor has only been developed recently and approved by the FDA for non-small cell lung cancer. However, the inhibitor demonstrated much lower response rates in CRC (<20%) than other cancer types. Thus, developing effective therapies for KRAS mutant (KRASm) CRC still remains challenging. Oncogenic KRAS signaling has been shown to have immunosuppressive effects on tumor microenvironment, thus we hypothesized that KRAS inhibitor can indirectly enhance antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. Indeed, using a syngeneic KRASG12C CRC mouse model with knockout of APC, TP53, SMAD4 and expressing KRASG12C, we observed significant increase in the percentage of CD3+CD8+ T cells as well as changes in myeloid populations in tumors treated with KRASG12C inhibitor compared with vehicle control. Combination of KRASG12C/PD-1 inhibition produced a more substantial and sustained reduction in tumor growth compared with KRAS or PD-1 inhibition alone. KRASG12C CRC mouse model represents a proper tool to study tumor cell-intrinsic mechanism of cooperativity between KRAS inhibition and immune response, since KRASG12C inhibitor targets KRASm tumor cells only without having direct effects on stromal and immune cells. Interestingly, we found tumor-intrinsic immune programs induction by KRAS/MAPK inhibition in KRASG12C CRC mouse models and patient-derived organoid models. We also found that KRASG12C inhibition upregulates T-cell recruiting chemokines CXCL9 and CXCL10 via IRF1 in KRASm tumor cells, which might be one of the potential mechanisms underlying enhanced infiltration of CD3+CD8+ T cells. These data suggest a link between KRAS inhibition and anti-tumor immunity, thus provide insights into novel combination strategies for KRASG12C colorectal cancers. Citation Format: Jun Tian, Ferran Fece de la Cruz, Kelly Burke, Tomonori Oka, Jacquelyn M. Curtis, Princy Sindurakar, Edmond Wong, Shadmehr Demehri, Arlene Sharpe, Ryan Corcoran. KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB352.