Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer
KRAS G12C inhibitors (G12Cis) have revolutionized the treatment of cancers driven by this historically undruggable mutation, offering unprecedented clinical responses in non‑small cell lung cancer (NSCLC).
KRAS G12C inhibitors have transformed treatment of KRAS‐mutated NSCLC but both primary and acquired resistance limit their clinical efficacy. The review summarizes the diverse mechanisms of resistance, with a focus on how co‑mutations in tumour suppressor genes (TSGs) such as STK11, KEAP1, TP53 and CDKN2A/B drive resistance through sustained proliferation, metabolic reprogramming, phenotypic plasticity and immune micro‑environmental remodeling. Clinical data from CodeBreak, KRYSTAL‑1 and other trials are discussed alongside pre‑clinical models that illustrate the functional impact of TSG loss on KRAS G12C inhibitor response.
Understanding how tumour‑suppressor‑gene alterations contribute to KRAS G12C inhibitor resistance will guide the design of combination therapies and biomarker‑driven clinical strategies to improve outcomes for patients with KRAS‐mutated NSCLC.
Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.
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