2. Academic Validation
  3. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

  • Cancer Cell. 2019 Nov 11;36(5):545-558.e7. doi: 10.1016/j.ccell.2019.09.004.
Victor Quereda 1,  Simon Bayle 1,  Francesca Vena 1,  Sylvia M Frydman 1,  Andrii Monastyrskyi 1,  William R Roush 2,  Derek R Duckett 3
Affiliations

Affiliations

  • 1 Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 2 Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • 3 Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: [email protected].
PMID: 31668947 DOI: 10.1016/j.ccell.2019.09.004
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.

Keywords

BRCAness; CDK12; CDK13; PARP inhibitor; cisplatin; intronic polyadenylation; triple-negative breast cancer.

Figures
Products