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Ref Type Journal Article
PMID (32668240)
Authors Shan W, Yuan J, Hu Z, Jiang J, Wang Y, Loo N, Fan L, Tang Z, Zhang T, Xu M, Pan Y, Lu J, Long M, Tanyi JL, Montone KT, Fan Y, Hu X, Zhang Y, Zhang L
Title Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment.
Journal Cell reports
Vol 32
Issue 2
Date 2020 Jul 14
URL
Abstract Text Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies.

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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
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 ovarian cancer not applicable Olaparib + THZ1 Preclinical - Cell culture Actionable In a preclinical study, treatment with Lynparza (olaparib) combined with THZ1 resulted in a synergistic effect in homologous recombination-proficient ovarian cancer cells, demonstrating decreased cell survival and reduced anchorage-independent growth in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 32668240). 32668240
Unknown unknown prostate cancer not applicable Olaparib + THZ1 Preclinical - Cell culture Actionable In a preclinical study, treatment with Lynparza (olaparib) combined with THZ1 resulted in a synergistic effect in homologous recombination-proficient prostate cancer cells, demonstrating decreased cell survival and reduced anchorage-independent growth in culture (PMID: 32668240). 32668240
Unknown unknown triple-receptor negative breast cancer not applicable Olaparib + THZ1 Preclinical - Cell line xenograft Actionable In a preclinical study, Lynparza (olaparib) treatment combined with THZ1 resulted in a synergistic effect in homologous recombination-proficient triple-receptor negative breast cancer cells, demonstrating decreased cell survival and anchorage-independent growth in culture, and inhibition of tumor growth in cell line xenograft models (PMID: 32668240). 32668240