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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 Cancer cell
Vol 36
Issue 5
Date 2019 Nov 11
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
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
Unknown unknown triple-receptor negative breast cancer not applicable Cisplatin + SR-4835 Preclinical - Pdx Actionable In a preclinical study, SR-4835 and Platinol (cisplatin) combination treatment induced apoptosis, inhibited proliferation and tumor growth, leading to tumor regression in an orthotopic patient-derived xenograft (PDX) model of triple-negative breast cancer (PMID: 31668947). 31668947
Unknown unknown triple-receptor negative breast cancer not applicable SR-4835 Preclinical - Pdx Actionable In a preclinical study, SR-4835 treatment induced DNA damage and cell death, and inhibited tumor growth in a patient-derived xenograft (PDX) model of triple-negative breast cancer harboring a BRCA1 mutation (PMID: 31668947). 31668947
Unknown unknown triple-receptor negative breast cancer not applicable Irinotecan + SR-4835 Preclinical - Pdx Actionable In a preclinical study, SR-4835 and Camptosar (irinotecan) combination treatment induced DNA damage and cell death, inhibited tumor growth, leading to tumor regression in a patient-derived xenograft (PDX) model of triple-negative breast cancer harboring a BRCA1 mutation (PMID: 31668947). 31668947