Cancer Cell
Volume 36, Issue 5, 11 November 2019, Pages 545-558.e7
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Article
Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

https://doi.org/10.1016/j.ccell.2019.09.004Get rights and content
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Highlights

  • SR-4835, a potent dual inhibitor of CDK12/CDK13, provokes TNBC cell death

  • CDK12/CDK13 inhibition/loss promotes cleavage at intronic polyadenylation sites

  • CDK12 inhibition causes a BRCAness phenotype by blocking homologous recombination

  • SR-4835 acts in synergy with DNA-damaging chemotherapy and PARP inhibitors

Summary

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

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

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