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|Ref Type||Journal Article|
|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.|
|Date||2019 Nov 11|
|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.|
|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||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||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||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|