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Targeting CDK12/13 Drives Mitotic Arrest to Overcome Resistance to KRASG12C Inhibitors
Yaakov E Stern1, Pompom Ghosh2, John Peroza1
1Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Cancer Research
|October 30, 2025
Summary
Acquired resistance to KRASG12C inhibitors in lung cancer can be overcome by targeting CDK12/13. Combining KRAS and CDK12/13 inhibitors, like sotorasib and SR-4835, suppresses resistance and extends treatment response duration.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Acquired resistance to KRASG12C inhibitors is a major challenge in lung cancer treatment.
- Activation of DNA repair pathways and G2/M kinases is observed in resistant lung cancers.
Purpose of the Study:
- To identify vulnerabilities in KRASG12C-mutant lung cancer with acquired resistance.
- To evaluate the efficacy of combining KRAS inhibitors with CDK12/13 inhibitors.
Main Methods:
- Utilized KRASG12C-mutant cell lines with acquired resistance to sotorasib.
- Administered the CDK12/13 selective inhibitor SR-4835.
- Assessed DNA repair gene expression, cell cycle arrest, and TP73 isoform levels.
- Evaluated combined treatment effects in cell culture and mouse models.
Main Results:
- CDK12/13 inhibition suppressed DNA repair and induced mitotic arrest in resistant cells.
- Combined sotorasib and SR-4835 showed additive effects and suppressed acquired resistance.
- Combination therapy extended response duration compared to single agents in preclinical models.
Conclusions:
- Targeting CDK12/13 presents a promising strategy to overcome or prevent resistance to KRAS inhibitors in lung cancer.
- Combination therapy with KRAS and CDK12/13 inhibitors may extend treatment duration.
- Patients with acquired resistance may benefit from subsequent CDK12/13 inhibitor monotherapy.
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