Targeted therapeutic strategies for KRAS-G12D-mutant non-small cell lung cancer: a narrative review

Kirsten rat sarcoma viral oncogene homolog (KRAS)-G12D is a common oncogenic mutation in non-small cell lung cancer (NSCLC) and has posed significant challenges in the development of treatment approaches that specifically target this alteration. KRAS-G12D differs from KRAS-G12C in its biochemical and signal transduction features, which limits the use of drugs targeting the KRAS-G12C mutation, creating substantial demands in clinical contexts. This review sought to summarize the major developments in treatment for KRAS-G12D-mutant NSCLC, with a focus on the recent key advances and emerging clinical data on targeted therapies.

A comprehensive literature search was conducted using electronic databases, including PubMed, Web of Science, and Google Scholar, supplemented by manual searching of reference lists and related articles. The review focused on preclinical and clinical research on KRAS-G12D-targeted therapies and indirect regulatory inhibitors.

Rapid progress has been made in development of therapies targeting KRAS-G12D. A variety of direct-targeting strategies, including allele-selective non-covalent inhibitors, RAS in the active guanosine triphosphate (GTP) state [RAS (ON)] selective inhibitors, and targeted protein degradation (TPD) agents, have shown the feasibility of inhibiting the KRAS-G12D signaling pathway in preclinical and early clinical studies. The indirect inhibition of upstream regulators, such as son of sevenless homolog 1 (SOS1) and Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2), and the blocking of downstream pathways have also provided important treatments that combine multiple approaches. In addition, co-mutation patterns, the tumor immune microenvironment, and adaptive resistance mechanisms significantly influence therapeutic responses and clinical outcomes.

Driven by diverse drug discovery platforms and mechanism-based combination strategies, KRAS-G12D targeting is rapidly transitioning from conceptual validation to clinical application. These advances provide new opportunities for the precision treatment of NSCLC.