KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations represent the most common driver alterations in non-small cell lung cancer and were long considered "undruggable" due to the lack of a suitable binding pocket on the protein surface. Recent structural breakthroughs have identified the Switch-II allosteric pocket, facilitating the development and clinical application of several covalent inhibitors—including Sotorasib, Adagrasib, and Divarasib—which have substantially improved outcomes for patients harboring this mutation. However, primary and acquired resistance remain major obstacles to long-term efficacy, with resistance mechanisms involving RTK-mediated adaptive signaling reactivation, aberrant PI3K–AKT–mTOR pathway activation, secondary genetic alterations, and other factors. Moreover, intratumoral heterogeneity, characterized by the coexistence of sensitive and resistant subclones, further complicates therapeutic responses. To overcome these challenges, combination strategies have become a major research focus, including the pairing of KRAS G12C inhibitors with immune checkpoint inhibitors, RTK-targeted agents, SHP2 inhibitors, or MEK inhibitors, aiming to block escape pathways and enhance antitumor immunity. Future directions emphasize optimizing combination regimens, exploring personalized immunotherapy, and developing next‑generation inhibitors to prolong survival. This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision‑making and further research in this field.