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

• Published in: Cancer cell 2019-11, Vol.36 (5), p.545-558.e7
• Main Authors: Quereda, Victor, Bayle, Simon, Vena, Francesca, Frydman, Sylvia M., Monastyrskyi, Andrii, Roush, William R., Duckett, Derek R.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; BRCAness; CDC2 Protein Kinase - metabolism; CDK12; CDK13; Cell Line, Tumor; cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - metabolism; DNA Damage - drug effects; Drug Synergism; Epigenesis, Genetic - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Homologous Recombination - drug effects; Humans; intronic polyadenylation; Introns - drug effects; Introns - genetics; Mice; PARP inhibitor; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Polyadenylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; triple-negative breast cancer; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2019.09.004

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. [Display omitted] •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 Quereda et al. develop a selective dual CDK12/CDK13 inhibitor that reduces the expression of core DNA damage response genes by increasing intronic polyadenylation site cleavage, resulting in DNA damage repair deficiency and conferring sensitivity to DNA-damaging agents and PARP inhibitors.