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Small molecular inhibitors for KRAS-mutant cancers

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FRONTIERS IN IMMUNOLOGY
卷 14, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2023.1223433

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RAS mutation; different isoform; RAS inhibitor; immunotherapy; combination strategy

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Three isoforms of RAS gene, KRAS, NRAS, and HRAS, are the most mutated family of small GTPases in cancer. While targeted immunotherapies have improved the survival of patients with non-KRAS-mutant cancer, RAS-mutant cancers still have a poor prognosis due to their high aggressiveness. However, recent advances in the use of allele-specific covalent inhibitors have led to the development of effective pharmacological interventions against RAS-mutant cancer, such as Sotorasib (AMG510) for KRAS-G12C mutant NSCLC. This review summarizes the progress and promise of small-molecule inhibitors in clinical trials to improve the prognosis of tumors with RAS mutations.
Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered undruggable, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.

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