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.
- 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].
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.