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

Publication date: Available online 24 October 2019Source: Cancer CellAuthor(s): Victor Quereda, Simon Bayle, Francesca Vena, Sylvia M. Frydman, Andrii Monastyrskyi, William R. Roush, Derek R. DuckettSummaryEpigenetic 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research