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    BIOMARKER:

    CDK12 mutation

    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
    Entrez ID:
    51755
    Related biomarkers:
    Mutation
    CNA
    Related tests:
    1d
    Roles of CDK12 mutations in PCa development and treatment. (PubMed, Biochim Biophys Acta Rev Cancer)
    Due to the poor prognosis of CDK12-mutant PCa patients and the mediocre response to classic standard therapies, HRD and increased neoantigen levels have provided clinicians with new insights into alternative systematic treatments for this novel PCa phenotype. In this review, we summarize the roles of CDK12 mutations in PCa and discuss their clinical value, suggesting that CDK12 potentially represents a target for further research and the development of clinical strategies for PCa.
    Review • Journal
    |
    AR (Androgen receptor) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)
    |
    HRD • CDK12 mutation • MYC expression
    27d
    Association between homologous recombination deficiency and time to treatment failure to platinum-based chemotherapy for pancreatic cancer by using the C-CAT database. (PubMed, J Gastroenterol)
    Our findings suggest that HRR-related genetic abnormalities might be predictive of TTF in platinum-based chemotherapy for PC.
    Journal • BRCA Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1)
    |
    HRD • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • BARD1 mutation
    |
    FoundationOne® CDx • OncoGuide™ NCC Oncopanel System
    |
    gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • irinotecan • leucovorin calcium
    29d
    Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer. (PubMed, Nat Cancer)
    Inhibition of WEE1, CHK1 and ATR selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form as a result of TRCs and their presence can be used as a biomarker for prognosis and treatment.
    Journal
    |
    TP53 (Tumor protein P53) • CDK12 (Cyclin dependent kinase 12) • SPOP (Speckle Type BTB/POZ Protein) • CHEK1 (Checkpoint kinase 1)
    |
    TP53 mutation • CDK12 mutation
    2ms
    The landscape of genomic alterations and their phenotype associations in high-risk localized prostate cancer in the Genomic Umbrella Neoadjuvant Study (PCF 2024)
    Transcriptomes distinguished ETS -fused tumors from SPOP mutants, and PTEN loss from PTEN/AKT1 mutations. Inferred relationships between specific genomic alterations and gene expression signatures of luminal/basal subtypes and of biological pathways/processes, including AR signaling, proliferation, and plasticity signatures, provide a basis to understand differences in treatment response and inform biomarker-guided treatment strategies.
    Clinical • BRCA Biomarker
    |
    TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CDK12 (Cyclin dependent kinase 12) • ERG (ETS Transcription Factor ERG) • SPOP (Speckle Type BTB/POZ Protein) • FOXA1 (Forkhead Box A1) • TMPRSS2 (Transmembrane serine protease 2)
    |
    CDK12 mutation • AKT1 mutation • AR expression • SPOP mutation • TMPRSS2-ERG fusion • FOXA1 mutation
    |
    Prosigna™ Breast Cancer Prognostic Gene Signature Assay
    3ms
    Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase. (PubMed, Glycobiology)
    Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome.
    Journal
    |
    CDK12 (Cyclin dependent kinase 12) • SRPK1 (SRSF Protein Kinase 1)
    |
    CDK12 mutation
    3ms
    Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer. (PubMed, NPJ Precis Oncol)
    This is the largest study to investigate the distinct genomic landscape of CDH1-MT GC. Our data indicated GC patients with CDH1 mutations could potentially benefit from agents targeting PARP and Wee1.
    Journal • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
    |
    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • CDK12 (Cyclin dependent kinase 12) • APC (APC Regulator Of WNT Signaling Pathway) • CDH1 (Cadherin 1) • IGF1R (Insulin-like growth factor 1 receptor) • CRKL (CRK Like Proto-Oncogene, Adaptor Protein) • WRN (WRN RecQ Like Helicase) • POT1 (Protection of telomeres 1) • FANCC (FA Complementation Group C)
    |
    TP53 mutation • HER-2 amplification • ARID1A mutation • CDK12 mutation • CDH1 mutation • WRN mutation • CRKL amplification • IGF1R amplification
    3ms
    CHANGEABLE: Combination of HX008 And Niraparib in GErm-line-mutAted Metastatic Breast Cancer (clinicaltrials.gov)
    P2, N=37, Completed, Fudan University | Recruiting --> Completed
    Trial completion • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • BAP1 (BRCA1 Associated Protein 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • WRN (WRN RecQ Like Helicase) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
    |
    HER-2 positive • BRCA2 mutation • BRCA1 mutation • HR positive • HER-2 negative • ATM mutation • PALB2 mutation • CDK12 mutation • BAP1 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • HR positive + HER-2 negative • RAD50 mutation • BARD1 mutation • BLM mutation • CHEK1 mutation • FANCF mutation • MRE11A mutation • NBN mutation • FANCM mutation • PTEN mutation + HR positive • CHEK1 expression • HER-2 negative + HR positive + BRCA mutation
    |
    Herceptin (trastuzumab) • Zejula (niraparib) • Puyouheng (pucotenlimab)
    3ms
    Synthetic Lethal Targeting of Cyclin Dependent Kinase-12-Deficient Prostate Cancer with PARP Inhibitors. (PubMed, Clin Cancer Res)
    In PC, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in PC patients with biallelic inactivating CDK12 alterations.
    Journal • PARP Biomarker • Synthetic lethality
    |
    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    |
    CDK12 mutation
    |
    Rubraca (rucaparib)
    3ms
    Ipilimumab with Nivolumab in molecular-Selected patients with castration-resistant PRostate cancer: primary analysis of the Phase 2 INSPIRE trial. (PubMed, Ann Oncol)
    This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR>6 in 40% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm and CDK12i subgroups, but demonstrated exceptional efficacy in MMRd.
    P2 data • Journal • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
    |
    TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12)
    |
    BRCA2 mutation • CDK12 mutation
    |
    Opdivo (nivolumab) • Yervoy (ipilimumab)
    3ms
    Circulating Tumor DNA (ctDNA) Monitoring in the Assessment and Prediction of the Efficacy of PARP Inhibitors (PARPi) (clinicaltrials.gov)
    P=N/A, N=30, Recruiting, Sun Yat-sen University | Trial completion date: Aug 2023 --> Aug 2025
    Trial completion date • Circulating tumor DNA
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • BRCA1 mutation + ATM mutation • CHEK1 expression
    8ms
    Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer. (PubMed, Mol Cytogenet)
    These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • CDK12 (Cyclin dependent kinase 12) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • IDO1 (Indoleamine 2,3-dioxygenase 1)
    |
    PD-L1 expression • CDK12 mutation • IDO1 expression
    8ms
    Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations. (PubMed, Clin Genitourin Cancer)
    Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.
    Clinical data • Journal • BRCA Biomarker • Metastases
    |
    BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)
    |
    ATM mutation • CDK12 mutation
    8ms
    Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes (clinicaltrials.gov)
    P1, N=30, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting
    Enrollment open
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • RAD50 mutation • RAD51B mutation • BARD1 mutation • BLM mutation • FANCF mutation • MRE11A mutation • NBN mutation • FANCM mutation • RAD51 mutation
    9ms
    NIRADO: Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab (clinicaltrials.gov)
    P2, N=51, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=112 --> 51 | Trial completion date: Mar 2027 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Dec 2024
    Enrollment change • Trial completion date • Trial suspension • Trial primary completion date • Pan tumor
    |
    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)
    |
    HER-2 positive • HER-2 amplification • DDR • PBRM1 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • NBN mutation • DRD
    |
    Zejula (niraparib) • Jemperli (dostarlimab-gxly)
    9ms
    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, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=1000 --> 130 | Trial primary completion date: Apr 2024 --> Dec 2024
    Enrollment change • Trial primary completion date • Pan tumor
    |
    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)
    |
    DDR • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • NBN mutation • DRD
    |
    Tecentriq (atezolizumab) • Rubraca (rucaparib)
    9ms
    CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer. (PubMed, Sci Rep)
    These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.
    Journal • IO biomarker • Pan tumor • Immunomodulating
    |
    CDK12 (Cyclin dependent kinase 12)
    |
    CDK12 mutation
    10ms
    Genomic landscape of circulating tumor DNA in cervical cancer in Asia: NCCH1905/A-TRAIN trial (AACR 2024)
    Comprehensive genomic profiling using liquid biopsy can rapidly identify potential candidates for targeted therapy in cervical cancer patients, regardless of histopathology. Clinical studies of precision medicines in Asia are encouraged for such patients.
    BRCA Biomarker • Circulating tumor DNA
    |
    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • NOTCH1 (Notch 1) • CDK12 (Cyclin dependent kinase 12)
    |
    BRCA2 mutation • BRCA1 mutation • HER-2 amplification • PIK3CA mutation • HRD • ATM mutation • CDK12 mutation • HRD + BRCA1 mutation • ATM mutation + CDK12 mutation
    |
    Guardant360® CDx
    10ms
    ORCHID: Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations (clinicaltrials.gov)
    P2, N=20, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BAP1 (BRCA1 Associated Protein 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L)
    |
    BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • RAD51 mutation • CHEK1 expression
    |
    Lynparza (olaparib)
    10ms
    A Study Evaluating Safety and Efficacy of Niraparib in Patients With Previously Treated Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma (clinicaltrials.gov)
    P2, N=43, Active, not recruiting, Shadia Jalal, MD | Trial completion date: Nov 2024 --> Jul 2024 | Trial primary completion date: Nov 2023 --> Feb 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ARID1A (AT-rich interaction domain 1A) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • RAD54L mutation • NBN mutation
    |
    Zejula (niraparib)
    10ms
    A Study of Olaparib and Durvalumab in Prostate Cancer (clinicaltrials.gov)
    P2, N=5, Terminated, Memorial Sloan Kettering Cancer Center | Completed --> Terminated; Due to low accrual
    Trial termination • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1)
    |
    BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • BARD1 mutation • FANCA deletion
    |
    Lynparza (olaparib) • Imfinzi (durvalumab)
    10ms
    ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features. (PubMed, J Pathol Clin Res)
    ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12) • CDH1 (Cadherin 1) • SOX10 (SRY-Box 10)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 negative • HR negative • CDK12 mutation • CDH1 mutation • CDK12 amplification
    12ms
    Trans-Regulation of Alternative PD-L1 mRNA Processing by CDK12 in Non-Small-Cell Lung Cancer Cells. (PubMed, Cells)
    The fact that CDK12 regulates PD-L1 transcript variant formation in NSCLC cells is consistent with CDK12's role in promoting transcriptional elongation over intron-located poly-A sites. This study lays the groundwork for clinical investigations to delineate the implications of the CDK12-mediated balancing of sPD-L1 relative to mPD-L1 for immunotherapeutic responses in NSCLC.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • CDK12 (Cyclin dependent kinase 12)
    |
    PD-L1 expression • CDK12 mutation
    12ms
    Testing the Combination of the Anti-cancer Drugs Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors With Selected Mutations (clinicaltrials.gov)
    P1, N=108, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CD4 (CD4 Molecule) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
    |
    PIK3CA mutation • PTEN mutation • PALB2 mutation • CDK12 mutation • PIK3CA E545 • PIK3CA H1047 • BARD1 mutation • PIK3CA E542 • RAD51 mutation
    |
    Lynparza (olaparib) • Imfinzi (durvalumab) • Aliqopa (copanlisib)
    12ms
    Testing the Combination of the Anti-cancer Drugs Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors With Selected Mutations (clinicaltrials.gov)
    P1, N=108, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CD4 (CD4 Molecule) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
    |
    PIK3CA mutation • PTEN mutation • PALB2 mutation • CDK12 mutation • PIK3CA E545 • PIK3CA H1047 • BARD1 mutation • PIK3CA E542 • RAD51 mutation
    |
    Lynparza (olaparib) • Imfinzi (durvalumab) • Aliqopa (copanlisib)
    1year
    Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes (clinicaltrials.gov)
    P1, N=30, Suspended, National Cancer Institute (NCI) | Initiation date: Oct 2023 --> Jul 2023
    Trial initiation date
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • RAD51D mutation • RAD50 mutation • RAD51B mutation • BARD1 mutation • BLM mutation • FANCF mutation • MRE11A mutation • NBN mutation • FANCM mutation • RAD51 mutation
    1year
    Genomic mutations and homologous recombination deficiency (HRD) score in Japanese patients with metastatic hormone-sensitive prostate cancer (mHSPC): The impact of intraductal carcinoma of the prostate (IDC-P). (ASCO-GU 2024)
    Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.
    Clinical • BRCA Biomarker • Metastases
    |
    TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • FOXA1 (Forkhead Box A1)
    |
    TP53 mutation • HRD • PTEN mutation • CDK12 mutation • BRCA mutation • PTEN mutation + TP53 mutation • High HRD score
    |
    Myriad myChoice® CDx Plus
    1year
    The survival outcomes for men with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination deficiencies (HRD) treated with radium-223: Princess Margaret Cancer Centre (PMCC) experience. (ASCO-GU 2024)
    A total of 29 (72.5%) patients received 233 Ra following abiraterone or enzalutamide treatment while 10 (25%) received 233 Ra post docetaxel. While the number of patients included in our review was small, our analysis suggested that patients with HRD may have a slight improvement in OS after 223Ra treatment. Validation in a prospective dataset is required, and whether HRD status has implications for other radiopharmaceuticals such as lutetium-177 remains to be seen.
    BRCA Biomarker • Metastases
    |
    BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2)
    |
    HRD • CDK12 mutation • CHEK2 mutation
    |
    docetaxel • Xtandi (enzalutamide) • abiraterone acetate • Xofigo (radium Ra-223 dichloride)
    1year
    Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial. (ASCO-GU 2024)
    BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820.NR, not reached; BRIP1, RAD51B, RAD51D n=1; CHEK1, RAD51C n=0.
    Clinical • PARP Biomarker • BRCA Biomarker • Metastases
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L)
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    ATM mutation • CDK12 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BRCA mutation • CHEK1 mutation • BRCA2 mutation + ATM mutation • CHEK1 expression
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    FoundationOne® CDx • FoundationOne® Liquid CDx
    |
    Lynparza (olaparib) • abiraterone acetate
    1year
    Real-world homologous recombination repair mutation (HRRm) testing patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States. (ASCO-GU 2024)
    Pts with confirmed mCRPC diagnosis, age ≥21 years, treated with olaparib monotherapy after exposure to abiraterone or enzalutamide, and with positive HRRm status were included. This real-world analysis highlights the need for earlier HRRm testing in pts with mCRPC to allow for optimal timing of novel treatment options that have shown efficacy in a biomarker-selected population. Most pts in this study were tested and diagnosed with HRRm many months after mCRPC diagnosis, at which point they had high levels of bone metastasis, multiple sites of distant metastases, and opioid use at the initiation of olaparib treatment. HRR testing in pts before or at the time of mCRPC would allow for olaparib therapy earlier in the disease course.
    Real-world evidence • Clinical • PARP Biomarker • BRCA Biomarker • Real-world • Metastases
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L)
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    BRCA1 mutation • ATM mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • CHEK1 expression
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    Lynparza (olaparib) • Xtandi (enzalutamide) • abiraterone acetate
    1year
    Genetic and clinical landscape of ER + /PR- breast cancer in China. (PubMed, BMC Cancer)
    In this study, we identified the clinical and genetic characteristics of ER + /PR- breast cancer patients in China. Distinct PR statuses indicated different biological processes of ER + breast cancer and survival outcomes. Future treatment strategies may need to be tailored for ER + /PR- patients.
    Journal • Tumor mutational burden
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    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PGR (Progesterone receptor) • TMB (Tumor Mutational Burden) • CDK12 (Cyclin dependent kinase 12)
    |
    HER-2 positive • TP53 mutation • ER positive • HER-2 negative • PIK3CA mutation • CDK12 mutation • PGR negative
    |
    MammaPrint • BluePrint
    1year
    Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53. (ASCO-GI 2024)
    Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD.
    BRCA Biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
    |
    KRAS mutation • BRCA1 mutation • HRD • ATM mutation • ARID1A mutation • PALB2 mutation • CDK12 mutation • BAP1 mutation • CHEK2 mutation • HRD + BRCA1 mutation • BRCA mutation • NBN mutation
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    FoundationOne® CDx
    1year
    Metastatic prostate cancer is associated with distinct higher frequency of genetic mutations at diagnosis. (PubMed, Urol Oncol)
    Patients with M1PCa demonstrated characteristic genetic mutations compared to M0PCa, which most often influenced androgen receptor signaling and is associated with worse survival. In addition, we identified distinct genetic mutations between castration sensitive and resistant M1PCa. These findings may be used to further our understanding and management of men with PCa.
    Journal • Tumor mutational burden • Metastases
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • CDK12 (Cyclin dependent kinase 12) • SPOP (Speckle Type BTB/POZ Protein) • FOXA1 (Forkhead Box A1)
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    TP53 mutation • PTEN mutation • CDK12 mutation • SPOP mutation
    1year
    The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response. (PubMed, Cancer Med)
    Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • BRCA Biomarker • IO biomarker
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    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • RAD51C (RAD51 paralog C)
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    PD-L1 expression • BRCA1 mutation • ATM mutation • CDK12 mutation • RAD51C mutation • BRCA2 mutation + ATM mutation • RAD51 mutation
    |
    MSK-IMPACT
    1year
    Testing the Combination of the Anti-cancer Drugs Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors With Selected Mutations (clinicaltrials.gov)
    P1, N=108, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1
    Phase classification • Metastases
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    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CD4 (CD4 Molecule) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
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    PIK3CA mutation • PTEN mutation • PALB2 mutation • CDK12 mutation • PIK3CA E545 • PIK3CA H1047 • BARD1 mutation • PIK3CA E542 • RAD51 mutation
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    Lynparza (olaparib) • Imfinzi (durvalumab) • Aliqopa (copanlisib)
    1year
    The role of DNA repair genes mutational status in prostate cancer treatment with androgen signaling blockade (EMUC 2023)
    Probably, the data obtained on the worst efficacy of enzalutamide after docetaxel in patients with mutations in  HRR genes can be attributed to the biological features of the influence of therapy methods on the course of the disease. In clinical practice, it is advisable to take into account the fact of the influence of previous treatment on the effectiveness of antiandrogenic therapy in choosing the sequence of treatment methods.
    BRCA Biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CHEK1 (Checkpoint kinase 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51B mutation • CHEK1 mutation • RAD54L mutation • CHEK1 expression
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    docetaxel • Xtandi (enzalutamide)
    1year
    Clinical aspects of prostate cancer in patients with germinal and somatic mutations in homologous recombination repair (HRR) genes (EMUC 2023)
    There was an advantage in PFS when prescribing docetaxel for BRCA1/2 and ATM mutations in comparison with other mutations (p = 0.038)...In the PROfound trial, the advantage of Olaparib in radiological PFS  was not specified for germinal or somatic mutations in group A (BRCA1, BRCA2, ATM) and in the general group (A and B – other HRR mutations),though 28 patients had mutation in more than 1 HRR gene...Besides, germline mutations may predispose to exclusive somatic changes - additional mutations and epigenetic changes. The identification of these features will allow to personalize approaches to therapy and its sequence in prostate cancer.
    Clinical • BRCA Biomarker • PARP Biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1)
    |
    BRCA1 mutation • ATM mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation
    |
    Lynparza (olaparib) • docetaxel
    1year
    Prediction of Resistance to Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers. (PubMed, J Nucl Med)
    Lu-PSMA-617 and Lu-PSMA I&T (collectively termed Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET-positive disease, but biomarkers for these agents remain incompletely understood... Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for Lu-PSMA-treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.
    Journal • Circulating tumor DNA
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    FGFR1 (Fibroblast growth factor receptor 1) • CCNE1 (Cyclin E1) • CDK12 (Cyclin dependent kinase 12)
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    FGFR1 amplification • CCNE1 amplification • CDK12 mutation
    |
    Pluvicto (lutetium Lu 177 vipivotide tetraxetan)
    1year
    MEDIOLA: A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors. (clinicaltrials.gov)
    P1/2, N=264, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2022 --> Sep 2025
    Trial completion date • Combination therapy • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • BRCA (Breast cancer early onset)
    |
    HER-2 negative • CDK12 mutation • BARD1 mutation
    |
    Avastin (bevacizumab) • Lynparza (olaparib) • Imfinzi (durvalumab)
    1year
    Clinical application and potential impact of liquid biopsy on the management of Chinese patients with metastatic castration-resistant prostate cancer (mCRPC): A territory-wide prospective analysis (ESMO Asia 2023)
    BRCA2 mutations were detected in 9 (25.0%) patients, 4 of whom were switched to a PARP inhibitor and benefited clinically. In a real-life situation, liquid biopsy could potentially impact physician practices as well as patient outcomes.
    Clinical • Tumor mutational burden • PARP Biomarker • MSi-H Biomarker • BRCA Biomarker • Liquid biopsy • Metastases • Biopsy
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • HRD (Homologous Recombination Deficiency) • DNMT3A (DNA methyltransferase 1) • CDK12 (Cyclin dependent kinase 12)
    |
    BRCA2 mutation • MSI-H/dMMR • CDK12 mutation • AR mutation
    |
    FoundationOne® Liquid CDx
    1year
    Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis (clinicaltrials.gov)
    P2, N=50, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2023 --> May 2023
    Enrollment closed • Trial primary completion date
    |
    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) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
    |
    BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • CHEK1 expression
    |
    Lynparza (olaparib)
    over1year
    CDK12 loss inhibits cell proliferation by regulating TBK1 in non-small cell lung cancer cells. (PubMed, Mol Cell Probes)
    CDK12 positively regulates the expression of the oncogene TBK1 in lung cancer cells. These results revealed that CDK12 affects the progression of non-small cell lung cancer through positive regulation of TBK1 expression, suggesting that CDK12 might be a potential molecular target for the treatment of non-small cell lung cancer.
    Journal
    |
    CDK12 (Cyclin dependent kinase 12) • TBK1 (TANK Binding Kinase 1)
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    CDK12 mutation