Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer

SIMPLE SUMMARY: v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting oncogenic KRAS is a major challenge in the treatment of non-small-cell lung cancer (NSCLC). While several covalent KRAS G12C inhibitors have emerged as a novel anti-KRAS therapy, the development of combined therapies involving the targeting of oncogenic KRAS plus other targeted drugs is still required given the vast heterogeneity of KRAS-mutated tumors. In this review, we summarize the biological and immunological characteristics of oncogenic KRAS-driven NSCLC and the preclinical and clinical evidence for mutant KRAS-targeted therapies. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible therapeutic strategies to overcome this drug resistance. ABSTRACT: Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.