KRAS Inhibitor-Induced Cancer Cell Death Enhances Sensitivity to Immune-Mediated Bystander Killing of Drug-Resistant Subclones.

The clinical benefit of therapies targeting the KRAS G12C mutation is substantially limited by the development of resistance through multiple mechanisms. Therefore, to achieve lasting benefit with these therapies, effective strategies to tackle the evolution of drug resistance are required. To investigate this, we developed a preclinical model that mimics the development of resistance to KRAS G12C inhibitors (G12Ci), such as adagrasib and RMC-4998. Treatment of tumors containing a minor subpopulation of resistant cancer cells with G12Ci led to their rapid outgrowth, replacing drug-sensitive cells within a few weeks. However, combining G12Ci with therapies that enhance immune responses, such as anti-PD-1 or SHP2 inhibitors, resulted in the elimination of resistant cells and durable complete responses, even though anti-PD-1 or SHP2 inhibitor monotherapy did not induce regression of resistant tumors in the absence of drug-sensitive cells. This bystander killing of resistant cells following targeting of drug-sensitive cells was dependent on an intact adaptive immune system. Mechanistically, these combination therapies led to profound remodeling of the tumor immune microenvironment, making it less immunosuppressive, and promoted cancer cell death that primed an immune response, with an influx of cytotoxic T lymphocytes recognizing tumor-associated antigens shared between G12Ci-resistant and -sensitive cancer cells. Promotion of immune-mediated bystander elimination of drug-resistant cells may provide a paradigm for tackling the problem of drug resistance in cancer more broadly. SIGNIFICANCE: Combination therapies that stimulate antitumor immunity promote immune-mediated bystander killing of KRAS-G12C inhibitor resistant subpopulations, providing a strategy to overcome drug resistance that might have relevance in broader therapeutic settings.