Cediranib plus KRASG12C inhibitors triggers replication stress and antitumor immunity

Covalent KRASG12C inhibitors such as sotorasib and adagrasib have transformed treatment for KRAS-mutant cancers, but their clinical benefit is limited by intrinsic and adaptive resistance. A new study published in Molecular Cancer reports a combination strategy designed to overcome that resistance, pairing KRASG12C inhibitors with the multi-target tyrosine kinase inhibitor cediranib.

To identify the combination, the researchers established cell models resistant to both sotorasib and adagrasib and used the adagrasib-resistant models for high-throughput drug screening. That screen identified cediranib as a potent agent that restores sensitivity to KRASG12C inhibition, according to the study’s results.

Mechanistically, the authors report that cediranib synergizes with KRASG12C inhibitors to enforce a durable blockade of ERK signaling and prevent the adaptive MAPK reactivation that otherwise blunts single-agent treatment. This sustained suppression leads to profound downregulation of ribonucleotide reductase subunit M2, or RRM2, a rate-limiting enzyme in deoxyribonucleoside triphosphate biosynthesis.

The resulting depletion of nucleotide pools triggers what the study describes as catastrophic replication stress and DNA damage in treated tumor cells. In other words, the combination does not simply shut off oncogenic signaling; it converts that shutdown into a metabolic and genotoxic crisis inside the cancer cell.

The clinical relevance of the RRM2 finding was assessed using TCGA datasets. The analysis confirmed that high RRM2 expression correlates with poor prognosis in KRAS-mutant lung adenocarcinoma and pancreatic adenocarcinoma cohorts, positioning RRM2 as a marker of aggressive disease in these tumor types.

This reprograms the tumor microenvironment by enhancing the infiltration and activation of cytotoxic CD8+ T cells, linking the metabolic vulnerability exposed by the drug pair to antitumor immunity.

The therapeutic efficacy and immune-remodeling effects of the combination were validated using patient-derived xenografts and immunocompetent syngeneic mouse models. In vivo, the combination achieved robust tumor regression with a favorable safety profile, according to the study’s results section.

The authors conclude that their findings define a druggable ERK–RRM2 axis that links metabolic vulnerabilities to antitumor immunity, and they highlight the combination of cediranib and KRASG12C inhibitors as a promising translational strategy to overcome resistance in KRAS-mutant cancers. As with any preclinical study, the findings derive from cell models, xenografts and mouse experiments, and clinical testing in patients would be needed to establish efficacy and safety in humans.

Subject of Research: Overcoming resistance to KRASG12C inhibitors through multi-target kinase inhibition via the ERK–RRM2 axis

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

Article References: Chen, Q.-A., Lin, W., Gao, Y., & He, J. (2026). Multi-target kinase inhibition overcomes KRASG12C inhibitor resistance and potentiates antitumor immunity via the ERK–RRM2 axis. Molecular Cancer. https://doi.org/10.1186/s12943-026-02820-5

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02820-5

Keywords: KRASG12C, cediranib, drug resistance, ERK signaling, RRM2, replication stress, cGAS-STING, CD8+ T cells, lung adenocarcinoma, pancreatic adenocarcinoma, combination therapy, sotorasib