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    GENE:

    CDK12 (Cyclin dependent kinase 12)

    i
    Other names: CDK12, Cyclin Dependent Kinase 12, Cdc2-Related Kinase, Arginine/Serine-Rich, Cell Division Cycle 2-Related Protein Kinase 7, Cell Division Protein Kinase 12, CDC2-Related Protein Kinase 7, Cyclin-Dependent Kinase 12, CRKRS, CRK7, CDC2 Related Protein Kinase 7, HCDK12, CrkRS, CRKR
    3d
    NIRADO: Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab (clinicaltrials.gov)
    P2, N=51, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Dec 2027 --> Feb 2025 | Suspended --> Terminated; Abandon of the partner, GSK
    Trial completion date • Trial termination • Pan tumor • Platinum sensitive
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    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ARID1A (AT-rich interaction domain 1A) • PBRM1 (Polybromo 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • ARID2 (AT-Rich Interaction Domain 2) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • DRD (DNA Repair Deficiency)
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    HER-2 positive • HER-2 amplification • DDR • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • BARD1 mutation
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    Zejula (niraparib) • Jemperli (dostarlimab-gxly)
    3d
    ARIANES: Efficacy and Safety of the Combination of Rucaparib (PARP Inhibitor) and Atezolizumab (Anti-PD-L1 Antibody) in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors (clinicaltrials.gov)
    P2, N=130, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | Suspended --> Terminated; Bankruptcy of partner: Clovis
    Trial termination • Pan tumor • Platinum sensitive
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • IL2 (Interleukin 2) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • DRD (DNA Repair Deficiency)
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    DDR • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • BARD1 mutation
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    Tecentriq (atezolizumab) • Rubraca (rucaparib)
    9d
    Development of FBXO22 Degraders and the Recruitment Ligand 2-Pyridinecarboxyaldehyde (2-PCA). (PubMed, J Am Chem Soc)
    Conjugating 2-PCA to various ligands successfully induced the FBXO22-dependent degradation of BRD4 and CDK12. Collectively, these chemical probes will facilitate the study of FBXO22 biology and broaden its applicability in the TPD.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • BRD4 (Bromodomain Containing 4)
    10d
    CDK12 Deficiency Induces BRD4S to Promote Cancer Metastasis by Enhancing Phase Separation and Chromatin Engagement. (PubMed, Cancer Res)
    Consistently, BRD4S drove cancer cell dissemination in vitro and metastasis in vivo, which could be blocked by BET or TGF-β signaling pathway inhibitors. Overall, this study identifies IPA usage at the BRD4 gene locus induced by CDK12 deficiency as a mechanism responsible for BRD4S genesis, which represents an important mechanism driving cancer metastasis and a potential target for therapeutic intervention in CDK12-deficient cancers.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • LTBP1 (Latent-transforming growth factor beta-binding protein 1) • TGFB1 (Transforming Growth Factor Beta 1) • BRD4 (Bromodomain Containing 4) • TGFB2 (Transforming Growth Factor Beta 2)
    22d
    BrUOG360: A phase Ib/II study of copanlisib in combination with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). (PubMed, Cancer Res Commun)
    Copa/R had a favorable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.
    P1/2 data • Journal
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • RAD51C (RAD51 paralog C)
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    Rubraca (rucaparib) • Aliqopa (copanlisib)
    23d
    PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer: Rationale, Mechanisms, and Clinical Applications. (PubMed, Eur Urol Oncol)
    Promising results have led to the approval of several PARPi agents as monotherapy or in combination with ARPIs in selected or unselected patients when chemotherapy is not clinically indicated. However, some questions remain regarding patient selection and treatment sequencing.
    Review • Journal • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12)
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    PALB2 mutation • CDK12 mutation
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    Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • Xtandi (enzalutamide) • Rubraca (rucaparib) • Xofigo (radium Ra-223 dichloride)
    24d
    Blood-based Genomic Alteration Signature for Predicting Progression-free Survival in De Novo Metastatic Hormone-Sensitive Prostate Cancer: A Real-World Study. (PubMed, Cancer Res Commun)
    The model also showed significant clinical relevance, with bTRPC-positive patients exhibiting shorter survival times under ADT and doublet therapy, although this disparity diminished with triplet therapy. These findings highlight the potential of ctDNA-based gene mutation analysis to guide personalized treatment strategies for mHSPC, offering a non-invasive alternative to tissue-based analyses and improving prognostic accuracy.
    Journal • Real-world evidence
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    TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • CDK12 (Cyclin dependent kinase 12)
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    TP53 mutation • PTEN mutation • CDK12 mutation
    1m
    CDK12 as a Potential Biomarker for Characterization of Circulating Tumor Cells in Epithelial Ovarian Tumors. (PubMed, Curr Mol Med)
    Hence, the study demonstrated the potential of CDK12 as a biomarker for future blood-based diagnosis and personalized treatment in epithelial ovarian tumor patients.
    Journal • Circulating tumor cells
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    CDK12 (Cyclin dependent kinase 12) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • EPCAM (Epithelial cell adhesion molecule)
    1m
    Targeting CDK12/13 Drives Mitotic Arrest to Overcome Resistance to KRASG12C Inhibitors. (PubMed, Cancer Res)
    Patients with acquired resistance to sotorasib may benefit from follow-up monotherapy with CDK12/13 inhibitors, the first of which recently entered clinical trials. Targeting CDK12/13 thus offers a promising strategy to overcome or prevent resistance to KRAS inhibitors.
    Journal
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    KRAS (KRAS proto-oncogene GTPase) • CDK12 (Cyclin dependent kinase 12) • TP73 (Tumor Protein P73)
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    KRAS mutation
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    Lumakras (sotorasib)
    1m
    HLA class I expression shapes the tumor immune microenvironment and influences prognosis in prostate cancer. (PubMed, Prostate Cancer Prostatic Dis)
    In PC, elevated HLA class I levels correlate with immune activity, molecular characteristics, and clinical outcomes. We suggest considering HLA expression as a supplementary marker of immune activity in PC, alongside genetic mutations and transcriptomic markers.
    Journal • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
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    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • HLA-A (Major Histocompatibility Complex, Class I, A) • CDK12 (Cyclin dependent kinase 12) • FOXA1 (Forkhead Box A1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)
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    TMB-H • MSI-H/dMMR
    1m
    CA209-76M: Nivolumab in Biochemically Recurrent dMMR Prostate Cancer (clinicaltrials.gov)
    P2, N=8, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Completed | N=15 --> 8 | Trial completion date: Jan 2026 --> Jul 2025 | Trial primary completion date: Jan 2026 --> Apr 2025
    Trial completion • Enrollment change • Trial completion date • Trial primary completion date • Tumor mutational burden • dMMR
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    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12)
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    MSI-H/dMMR • CDK12 mutation
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    Opdivo (nivolumab)
    2ms
    Olaparib for patients with tumors harboring alterations in homologous recombination repair genes: Results from the drug rediscovery protocol. (PubMed, Int J Cancer)
    In conclusion, PARPi sensitivity varies across HRR-genes, indicating that relying solely on an altered common mechanistic pathway is insufficient to predict response. Future studies should target specific HRR-genes to assess subgroup-specific benefits and determine proper use of molecular diagnostics.
    Journal • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • CHEK1 (Checkpoint kinase 1) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
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    Lynparza (olaparib)