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Ref Type Journal Article
PMID (31668947)
Authors Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR
Title Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 36 5 2019 Nov 11 545-558.e7 Cancer Cell
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SR-4835 SR-4835 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SR-4835 SR-4835 selectively inhibits CDK12 and CDK13, impairs DNA damage response, which potentially leads to inhibition of cell proliferation and tumor growth (PMID: 31668947).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References