Multi-target kinase inhibition overcomes KRASG12C inhibitor resistance and potentiates antitumor immunity via the ERK–RRM2 axis

Although covalent KRAS G12C inhibitors have transformed the treatment landscape for KRAS-mutant cancers, their clinical efficacy is limited by the prevalence of intrinsic and adaptive resistance. This study aims to identify novel therapeutic strategies to overcome this resistance and elucidate the underlying molecular mechanisms. Sotorasib- and adagrasib-resistant cell models were established, with the latter utilized for high-throughput drug screening. Transcriptomic profiling was conducted to uncover the molecular mechanisms underlying the synergy between KRAS G12C inhibitors and cediranib. The therapeutic efficacy and immune-remodeling effects of the identified combination were validated using patient-derived xenografts (PDX) and immunocompetent syngeneic mouse models. Clinical relevance was assessed using TCGA datasets. High-throughput screening identified the multi-target tyrosine kinase inhibitor cediranib as a potent agent that restores sensitivity to KRAS G12C inhibition. Mechanistically, cediranib synergizes with KRAS G12C inhibitors to enforce durable ERK signaling blockade and prevent adaptive MAPK reactivation. This sustained suppression leads to profound downregulation of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis. Consequently, nucleotide depletion triggers catastrophic replication stress and DNA damage. Analysis of TCGA datasets confirmed that high RRM2 expression correlates with poor prognosis in KRAS-mutant lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) cohorts. Crucially, the resulting genomic instability triggers the cGAS–STING pathway, reprogramming the tumor microenvironment by enhancing the infiltration and activation of cytotoxic CD8 + T cells. In vivo, the combination achieved robust tumor regression with a favorable safety profile. Our findings define a druggable ERK–RRM2 axis that links metabolic vulnerabilities to antitumor immunity. This study highlights the combination of cediranib and KRAS G12C inhibitors as a promising translational strategy to overcome resistance in KRAS-mutant cancers.