Immune vulnerabilities of mutant KRAS in pancreatic cancer

The 40-year desire to target the mutant Kirsten rat sarcoma (KRAS) gene (mKRAS) therapeutically is being realized with more and more broadly applicable and tumor-specific small-molecule inhibitors. Immunologically, mKRAS has equal desirability as a target. Tumor KRAS signaling plays a large role in shaping the immunosuppressive nature of the tumor microenvironment, especially in pancreatic cancer, leaving mKRAS inhibitors with potentially powerful immune modulatory capabilities that could be exploited in immunological-oncological combinations. mKRAS is itself an immunological antigen, a 'shared neoepitope' linked to the oncogenic process, validated biochemically and immunologically. Novel approaches in the clinic are taking advantage of the fact that mKRAS peptides are naturally processed and presented in tumors by the major histocompatibility complex (MHC).

Automated summary

The long-held desire to target the mutant KRAS gene therapeutically is being fulfilled with the development of small-molecule inhibitors. In addition to its role as a therapeutic target, KRAS also plays a crucial role in shaping the immunosuppressive nature of the tumor microenvironment. This opens up new possibilities for combination immunotherapy using mKRAS inhibitors.