Abstract
Simple Summaryv-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.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.
Highlights
Introduction published maps and institutional affilLung cancer is the leading cause of cancer-related death worldwide
We previously identified NT5E, encoding CD73, as a gene upregulated by Kirsten rat sarcoma viral oncogene (KRAS) mutations in nonsmall-cell lung cancer (NSCLC) cells [62]
Harboring KRAS G12C and LKB1 coalterations. These results suggest that NSCLC patients are sensitized to immune checkpoint inhibitors by the KRAS G12C inhibitors through tumor immune microenvironment reconditioning, as shown in preclinical models [10,81]
Summary
KRAS is the predominantly mutated member (85%), followed by NRAS (11%) and HRAS cancers; the mutation frequencies of RAS isoforms differ among human cancers. G12C mutationand is NSCLC the most common (41%) mainly in NSCLC, G12D and G12V mutation is the most common (41%) in NSCLC, whereas the KRAS G12D and G12V mutamutations are the major subtypes in colorectal and pancreatic cancers 1. Frequencies of KRAS mutation subtypes in NSCLC, colorectal cancer and pancreatic cancer.cancer. 1. Frequencies of KRAS mutation subtypes in NSCLC, colorectal cancer. KRAS amplification was shown to be a mechanism of resistance to EGFR-TKIs [28] These studies suggest that KRAS copy number alterations enhance oncogenic KRAS activity, leading to treatment resistance and a worse prognosis in KRAS-mutated NSCLC
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