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Gene Symbol CDK12
Synonyms CRK7 | CRKR | CRKRS
Gene Description CDK12, cyclin dependent kinase 12, is a key regulator of transcription elongation, regulates the expression of genes involved in DNA repair, and is required for the maintenance of genomic stability (PMID: 24554720; PMID: 22012619). Loss and/or inactivation of CDK12 has been commonly observed in many solid tumor types, including prostate (PMID: 29906450, PMID: 31640893), breast, ovarian, endometrial, uterine (PMID: 30104286), and is a likely tumor suppressor (PMID: 30319007).

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDK12 dec exp ovarian cancer sensitive Cisplatin Preclinical Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor veliparib (ABT-888) (PMID: 24554720). 24554720
CDK12 dec exp ovarian cancer sensitive Veliparib Preclinical - Cell culture Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor, Veliparib (ABT-888) (PMID: 24554720). 24554720
CDK12 dec exp ovarian cancer sensitive Melphalan Preclinical Actionable In a preclinical study, the depletion of CDK12 in an ovarian cancer cell line by siRNAs resulted in the depletion of BRCA1 and sensitized the cells to the cross-linking agents Alkeran (melphalan), Platinol (cisplatin), and the PARP inhibitor veliparib (ABT-888) (PMID: 24554720). 24554720
CDK12 G909E prostate cancer predicted - resistant Enzalutamide Preclinical - Cell culture Actionable In a preclinical study, expression of CDK12 G909E in prostate cancer cells was associated with increased growth in the presence of Xtandi (enzalutamide) in culture (PMID: 36129942). 36129942
CDK12 inact mut prostate cancer sensitive Olaparib Phase II Actionable In a Phase II trial (TOPARP-B), Lynparza (olaparib) treatment resulted in a composite overall response rate of 25.0% (5/20) and a RECIST objective response rate of 0% (0/18) in patients with castration-resistant prostate cancer harboring deleterious CDK12 mutations (PMID: 31806540; NCT01682772). 31806540
CDK12 inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) improved median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious mutations in homologous recombination repair genes who progressed on hormone therapy, HR for progression or death was 0.74 in CDK12-mutant patients (PMID: 32343890; NCT02987543). detail... 32343890 detail...
CDK12 inact mut prostate cancer sensitive Olaparib Guideline Actionable Lynparza (olaparib) is included in guidelines as second-line therapy post androgen receptor-directed therapy for patients with metastatic castration-resistant prostate cancer harboring pathogenic mutations in CDK12 (NCCN.org). detail...
CDK12 inact mut prostate cancer no benefit Rucaparib Phase II Actionable In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring a CDK12 mutation presumed to be inactivating, with no confirmed radiographic responses in 10 evaluable patients and a PSA response in 1 patient with biallelic CDK12 alterations in the overall population of 15 patients, and a clinical benefit rate of 20% (3/15) at 6 months and 7.1% (1/14) at 12 months (PMID: 32086346; NCT02952534). 32086346
CDK12 inact mut Advanced Solid Tumor predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 12% (13/113), clinical benefit rate (CBR) of 42% (47/113), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including CDK12 with a CBR of 28.6% (2/7), and with a CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (PMID: 37277454; NCT04497116). 37277454
CDK12 inact mut prostate cancer sensitive Enzalutamide + Talazoparib FDA approved Actionable In a Phase III trial (TALAPRO-2) that supported FDA approval, Talzenna (talazoparib) plus Xtandi (enzalutamide) improved median radiographic progression-free survival compared to enzalutamide plus placebo (27.9 vs 16.4 mo, HR 0.46, p=0.0003) in patients with metastatic castration-resistant prostate cancer harboring deficient homologous recombination repair genes including CDK12, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). detail... 37285865
CDK12 inact mut prostate cancer sensitive Enzalutamide + Talazoparib Guideline Actionable Talzenna (talazoparib) plus Xtandi (enzalutamide) is included in guidelines as systemic therapy for patients with metastatic castration-resistant prostate cancer harboring a pathogenic germline or somatic CDK12 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). detail...
CDK12 G909R prostate cancer predicted - resistant Enzalutamide Preclinical - Cell culture Actionable In a preclinical study, expression of CDK12 G909R in prostate cancer cells was associated with increased growth in the presence of Xtandi (enzalutamide) in culture (PMID: 36129942). 36129942
CDK12 mutant prostate cancer predicted - sensitive unspecified PD-1 antibody Case Reports/Case Series Actionable In a clinical study, 50% (2/4) of prostate cancer patients with mutant CDK12 responded to an unspecified checkpoint inhibitor immunotherapy and had a corresponding decrease in prostate specific antigen (PMID: 29906450). 29906450
CDK12 S1236fs triple-receptor negative breast cancer predicted - sensitive Olaparib Case Reports/Case Series Actionable In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment resulted in an unconfirmed partial response with a 33% tumor size reduction in a patient with metastatic triple negative breast cancer harboring a somatic CDK12 S1236fs mutation (PMID: 33119476; NCT03344965). 33119476