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Updated: Jan 4, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer
Victor Quereda1, Simon Bayle1, Francesca Vena1
1Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Abstract:
Epigenetic regulation enables tumors to respond to changing environments during tumor progression and metastases and facilitates treatment resistance. Targeting chromatin modifiers or catalytic effectors of transcription is an emerging anti-cancer strategy. The cyclin-dependent kinases (CDKs) 12 and 13 phosphorylate the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes. Here we report the development of SR-4835, a highly selective dual inhibitor of CDK12 and CDK13, which disables triple-negative breast cancer (TNBC) cells. Mechanistically, inhibition or loss of CDK12/CDK13 triggers intronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins. This provokes a "BRCAness" phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors.
Insights
A new drug, SR-4835, targets cyclin-dependent kinases (CDK12/13) to disable triple-negative breast cancer cells. This approach creates a "BRCAness" state, enhancing chemotherapy and PARP inhibitor effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Epigenetic regulation is crucial for tumor progression, metastasis, and treatment resistance.
- Targeting chromatin modifiers and transcription factors is a promising anti-cancer strategy.
- Cyclin-dependent kinases (CDKs) 12 and 13 regulate RNA polymerase II, impacting transcription and co-transcriptional processes.
Purpose of the Study:
- To develop a selective dual inhibitor for CDK12 and CDK13.
- To investigate the anti-cancer effects of inhibiting CDK12/13 in triple-negative breast cancer (TNBC).
- To elucidate the molecular mechanisms by which CDK12/13 inhibition affects cancer cells.
Main Methods:
- Development of SR-4835, a selective dual inhibitor of CDK12 and CDK13.
- Assessment of SR-4835's efficacy in disabling TNBC cells.
- Analysis of the impact of CDK12/13 inhibition on DNA damage response (DDR) protein expression and DNA repair pathways.
Main Results:
- SR-4835 effectively disables triple-negative breast cancer cells.
- Inhibition of CDK12/13 leads to intronic polyadenylation site cleavage.
- Suppressed expression of core DNA damage response proteins creates a "BRCAness" phenotype, impairing DNA repair.
Conclusions:
- SR-4835 is a potent dual inhibitor of CDK12/13 with anti-cancer activity.
- CDK12/13 inhibition induces synthetic lethality by creating a "BRCAness" phenotype.
- This strategy enhances the efficacy of DNA-damaging chemotherapy and PARP inhibitors in TNBC.
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