KRAS-mutated Non‑Small Cell Lung Cancer : The Cancer Journal
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
The clinical benefit of therapies targeting the KRAS G12C mutation is substantially limited by the development of resistance through multiple mechanisms. We developed a preclinical model that mimics the emergence of drug‑resistant KRAS G12C inhibitor (G12Ci) subpopulations. Treatment of tumors containing a minor subpopulation of resistant cells with G12Ci alone led to rapid outgrowth of the resistant compartment. However, combining G12Ci with immune‑enhancing therapies such as anti‑PD‑1 or SHP2 inhibitors resulted in 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 depended on an intact adaptive immune system and was accompanied by profound remodeling of the tumor immune microenvironment, making it less immunosuppressive and promoting cancer‑cell death that primed an adaptive immune response.
The study demonstrates that immune‑enhancing agents can reverse the adverse effect of KRAS‑G12C inhibitor monotherapy—namely the selection and expansion of resistant subclones—by inducing immune‑mediated bystander killing and durable tumor eradication.
Bizonyítékszint: Számítógépes vagy elméleti. Modellből vagy adatbányászatból származó jel.
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