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Resistance to KRAS^G12C Inhibitors in Non-Small Cell Lung Cancer.

ABSTRACT: KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRAS^G12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein's mutant structure and block KRAS^G12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRAS^G12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRAS^G12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRAS^G12C inhibitors in KRAS^G12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.

SUBMITTER: Blaquier JB

PROVIDER: S-EPMC8739760 | biostudies-literature |

REPOSITORIES: biostudies-literature

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