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    GENE:

    CDK12 (Cyclin dependent kinase 12)

    i
    6d
    The Clinical Pathological Characteristics and Prognostic Relevance of Homologous Recombination Repair Gene Mutations in Ovarian Cancer Patients: A Prospective Cohort Study. (PubMed, Obstet Gynecol Int)
    This study indicates that mutations in the HRR gene possess significant potential as a prognostic marker in OC. Our aim was to comprehensively explore how HRR gene mutations, including but not limited to BRCA, might influence the clinical course and survival of patients, shedding light on potential new avenues for personalized treatment strategies.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • MUC16 (Mucin 16, Cell Surface Associated) • RAD51 (RAD51 Homolog A) • MRE11A (MRE11 homolog, double strand break repair nuclease) • RAD54L (DNA Repair And Recombination Protein RAD54)
    |
    BRCA mutation
    24d
    Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition. (PubMed, J Med Chem)
    Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate cancer cells. Notably, YJZ5118 exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    25d
    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 2026 --> Mar 2028 | Trial primary completion date: Mar 2025 --> Mar 2027
    Trial completion date • Trial primary completion date
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    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)
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    ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation
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    Lynparza (olaparib)
    28d
    Discovery of 4-(2-(methylamino)thiazol-5-yl)pyrimidin-2-amine derivatives as novel cyclin-dependent kinase 12 (CDK12) inhibitors for the treatment of esophageal squamous cell carcinoma. (PubMed, Bioorg Chem)
    In addition, H63 exhibited favorable pharmacokinetic properties, good safety, and prominent anti-ESCC activity in vivo. The present study suggests that CDK12 is a promising target for ESCC treatment, and H63 is a promising candidate for further clinical development as an anti-ESCC drug.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
    1m
    UK-based clinical testing programme for somatic and germline BRCA1/2, ATM and CDK12 mutations in prostate cancer: first results. (PubMed, BMJ Oncol)
    BRCA2 and CDK12 somatic PVs do not appear to be mutually exclusive. BRCA1 does not appear to be a significant contributor to prostate cancer progression.
    Journal • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12)
    |
    CDK12 mutation
    1m
    Evaluating the genetic landscape of prostate cancer: new insights from BRCA1/2, ATM and CDK12 mutations. (PubMed, BMJ Oncol)
    No abstract available
    Journal • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12)
    |
    CDK12 mutation
    1m
    A case of testicular dysgenesis syndrome with squamous cell carcinoma of the prostate harboring a CDK12 mutation. (PubMed, IJU Case Rep)
    Early imaging studies should be considered, even if the patient's prostate-specific antigen level is low when dysuria persists despite medical treatment. To the best of our knowledge, this is the first reported case of primary squamous cell carcinoma with a CDK12 mutation in a patient with TDS.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
    |
    CDK12 mutation
    1m
    Prostate Ductal Adenocarcinoma Revisited: Clinicopathological and Genomic Characterization Identifies Heterogenous Group of Diseases with Implications for Patient Management. (PubMed, Mod Pathol)
    Our findings suggest that PDAs are clinically and genetically heterogeneous diseases. Understanding the heterogeneity of PDA is critically important in determining its biological potential and facilitating optimal patient management.
    Journal • BRCA Biomarker
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    BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • RB1 (RB Transcriptional Corepressor 1) • NF1 (Neurofibromin 1) • CDK12 (Cyclin dependent kinase 12) • ERCC2 (Excision repair cross-complementation group 2) • ERG (ETS Transcription Factor ERG) • FOXA1 (Forkhead Box A1) • TMPRSS2 (Transmembrane serine protease 2) • POC1B (POC1 Centriolar Protein B)
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    FGFR2 fusion
    2ms
    Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13. (PubMed, Eur J Med Chem)
    Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    2ms
    Mutations in homologous recombination repair genes in patients with metastatic endometrial cancer: association with clinical characteristics and prognosis. (PubMed, J Gynecol Oncol)
    Somatic HRR mutations are detected in 11.8% of metastatic EC. Compared with noncarriers, HRR mutation carriers in metastatic EC have higher proportions of endometrioid carcinoma, POLEmut, and dMMR subtypes, and unique metastatic patterns. However, the prognoses are similar regardless of HRR status.
    Journal • BRCA Biomarker
    |
    TP53 (Tumor protein P53) • 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)
    |
    TP53 mutation • MSI-H/dMMR • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • BARD1 mutation
    2ms
    Design, Synthesis, and Biological Evaluation of Novel Orally Available Covalent CDK12/13 Dual Inhibitors for the Treatment of Tumors. (PubMed, J Med Chem)
    Thus, the functional inhibition of CDK12/13 offers an attractive strategy to combat carcinogenesis, particularly for refractory and treatment-resistant cancers. Here, we report the discovery of compound 12b as a novel, potent, orally available covalent CDK12/13 dual inhibitor with a promising safety profile and robust in vivo antitumor properties.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
    2ms
    Investigating the role of cathepsins in breast cancer progression: a Mendelian randomization study. (PubMed, Front Oncol)
    Cathepsin Z can mediate the effects of PRX, CRY2, ADCY3, and PELATON on in situ breast cancer. These findings highlight the dual roles of cathepsins as potential risk and protective factors for breast cancer, underscoring their potential in diagnostic and therapeutic strategies.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12) • CTSS (Cathepsin S)
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    HER-2 positive • HER-2 negative
    2ms
    Comprehensive Genome Profiling Test in Japanese Patients With Castration-Resistant Prostate Cancer: A Single-Center Retrospective Study. (PubMed, Cureus)
    The CGP test revealed critical genetic mutations in patients with CRPC and highlighted the poor prognosis associated with CDK12 mutations. The results underscore the necessity for novel therapies tailored to these genetic profiles, emphasizing the role of the CGP in improving treatment personalization.
    Retrospective data • Journal • Tumor mutational burden • PD(L)-1 Biomarker
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • CDK12 (Cyclin dependent kinase 12)
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    TP53 mutation • TMB-H • CDK12 mutation
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    FoundationOne® CDx
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    Keytruda (pembrolizumab)
    2ms
    Pembrolizumab, Olaparib, and Temozolomide for People with Glioma (clinicaltrials.gov)
    P2, N=57, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026
    Trial completion date • Trial primary completion date
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    EGFR (Epidermal growth factor receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • FGFR (Fibroblast Growth Factor Receptor) • CDK12 (Cyclin dependent kinase 12) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • 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)
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    CDKN2A deletion • BRIP1 mutation • RAD51C mutation • RAD51B mutation • BARD1 mutation • IDH wild-type
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    Keytruda (pembrolizumab) • Lynparza (olaparib) • temozolomide
    2ms
    Phase II Study of PARP Inhibitor Olaparib and IV Ascorbate in Castration Resistant Prostate Cancer (clinicaltrials.gov)
    P2, N=4, Terminated, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=15 --> 4 | Trial completion date: Mar 2028 --> Oct 2024 | Recruiting --> Terminated | Trial primary completion date: Mar 2028 --> Oct 2024; The study was terminated by the IRB due to low accrual,
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date
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    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) • FANCL (FA Complementation Group L)
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    FoundationOne® Liquid CDx
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    Lynparza (olaparib)
    2ms
    Morphologic Correlations With Homologous Recombination Deficiency in High-grade Serous Carcinomas. (PubMed, Int J Gynecol Pathol)
    In conclusion, HGSC with HRD, regardless of BRCA1/2-status, was associated with SET-like morphology and more severe nuclear atypia. Identifying and reporting these patterns of tumor morphology can prompt genomic profiling with prognostic, therapeutic, and genetic counseling implications.
    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) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • FANCC (FA Complementation Group C)
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    HRD • ATM mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation
    2ms
    Heterogeneity of the Treatment Effect with PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer: A Living Interactive Systematic Review and Meta-analysis. (PubMed, Eur Urol)
    Our LMA delivers information on the effect of PARPi therapy in relation to specific gene alterations in mCRPC via an interactive web platform. The evidence suggests the greatest PARPi benefit in patients with BRCA alterations, a strong signal of benefit in patients with PALB2 or CDK12 alterations, and no benefit in patients with ATM or CHEK2 alterations.
    Retrospective data • Review • 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) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2)
    2ms
    Association between DNA damage repair alterations and outcomes to 177Lu-PSMA-617 in advanced prostate cancer. (PubMed, ESMO Open)
    DDR alterations were not associated with outcomes following LuPSMA. This has implications for treatment sequencing in mCRPC, particularly in patients with DDR alterations.
    Journal • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • RAD51 (RAD51 Homolog A)
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    ATM mutation • PALB2 mutation • CDK12 mutation
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    Pluvicto (lutetium Lu 177 vipivotide tetraxetan)
    3ms
    Impacts of genomic alterations on the efficacy of HER2-targeted antibody-drug conjugates in patients with metastatic breast cancer. (PubMed, J Transl Med)
    Amplification in cell cycle genes may contribute to primary resistance of HER2 ADC in HER2-low breast cancer. ERBB2/CDK12 co-amplification may be a potential biomarker for favorable responses in HER2-positive breast cancer.
    Journal
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    TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDK12 (Cyclin dependent kinase 12)
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    HER-2 positive • HER-2 amplification
    3ms
    Abemaciclib With or Without Atezolizumab for mCRPC (clinicaltrials.gov)
    P2, N=75, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Dec 2024 --> Jun 2024
    Trial primary completion date
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    CDK12 (Cyclin dependent kinase 12)
    |
    Tecentriq (atezolizumab) • Verzenio (abemaciclib)
    3ms
    Pembrolizumab, Olaparib, Recurrent/Advanced Gastric and Gastro-esophageal Junction(GEJ) Cancer (clinicaltrials.gov)
    P1/2, N=71, Recruiting, Yonsei University | Not yet recruiting --> Recruiting | Trial completion date: May 2023 --> May 2025 | Trial primary completion date: Dec 2022 --> Dec 2024
    Enrollment open • Trial completion date • Trial primary completion date
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    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • 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)
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    HER-2 positive • BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • CHEK1 expression
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    Keytruda (pembrolizumab) • Lynparza (olaparib) • paclitaxel
    3ms
    Alterations in DNA Damage Repair Genes Before and After Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. (PubMed, Eur Urol Open Sci)
    Patients with muscle-invasive bladder cancer who have mutations in genes that are involved in repair of DNA damage are more likely to respond to cisplatin-based chemotherapy. Testing to identify these gene mutations could help in selecting the patients who are most likely to benefit from this treatment.
    Journal • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MLH1 (MutL homolog 1) • CDK12 (Cyclin dependent kinase 12) • ERCC2 (Excision repair cross-complementation group 2) • MSH3 (MutS Homolog 3) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • REV3L (REV3 Like DNA Directed Polymerase Zeta Catalytic Subunit) • SLX4 (SLX4 Structure-Specific Endonuclease Subunit)
    |
    CDK12 mutation • NBN mutation
    |
    cisplatin
    4ms
    Emerging molecular phenotypes and potential therapeutic targets in esophageal and gastric adenocarcinoma unearthed by whole genome and transcriptome analyses. (PubMed, Pathol Res Pract)
    Our findings support the potential of whole genome and transcriptome sequencing analyses as a comprehensive approach to identify treatment targets in adenocarcinoma of the stomach and the esophagus, and their application in precision oncology.
    Journal
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    ALK (Anaplastic lymphoma kinase) • HRD (Homologous Recombination Deficiency) • NRG1 (Neuregulin 1) • CDK12 (Cyclin dependent kinase 12) • RAD51B (RAD51 Paralog B) • NTRK (Neurotrophic receptor tyrosine kinase)
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    HRD • NRG1 fusion • RAD51B mutation • MET fusion
    4ms
    Novel structural variants that impact cell cycle genes are elucidated in metastatic gastrointestinal stromal tumors. (PubMed, Pathol Res Pract)
    Likewise, new structural variations were identified in cyclin-dependent kinase 12 (CDK12). Whole genome profiling of metastatic GIST provides new insights to advance precision care of the disease, focusing on new therapeutic possibilities, especially for emerging targets such as CDK12.
    Journal • Stroma • Metastases
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    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDK12 (Cyclin dependent kinase 12) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CDK2 (Cyclin-dependent kinase 2)
    4ms
    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
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    AR (Androgen receptor) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)
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    HRD • CDK12 mutation • MYC expression
    4ms
    Enhancing the detection of clinically relevant biomarkers in advanced uterine and tubo-ovarian carcinomas through genome-wide analysis. (PubMed, Pathol Res Pract)
    Comprehensive genomic profiling of advanced-stage TOC and UC via WGS reveals key biomarkers and therapeutic targets, enhancing diagnostic accuracy and advancing personalized medicine in gynecological cancers.
    Journal • Tumor mutational burden • BRCA Biomarker • PARP Biomarker • Metastases
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    TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CCNE1 (Cyclin E1) • CDK12 (Cyclin dependent kinase 12)
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    TMB-H • HRD • BRCA wild-type • CCNE1 amplification
    4ms
    Screening of a kinase inhibitor library identified novel targetable kinase pathways in triple-negative breast cancer. (PubMed, Anticancer Drugs)
    These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12) • EGF (Epidermal growth factor) • CDK7 (Cyclin Dependent Kinase 7) • CDK13 (Cyclin Dependent Kinase 13)
    4ms
    Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations (clinicaltrials.gov)
    P2, N=36, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026
    Trial completion date • Trial primary completion date • Metastases
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    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) • BAP1 (BRCA1 Associated Protein 1) • 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) • 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)) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCF (FA complementation group F) • FANCL (FA Complementation Group L) • FANCI (FA Complementation Group I) • FANCM (FA Complementation Group M) • BACH1 (BTB Domain And CNC Homolog 1) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCG (FA Complementation Group G) • FANCB (FA Complementation Group B) • FANCC (FA Complementation Group C)
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    BRCA2 mutation • BRCA1 mutation • ATM mutation
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    Talzenna (talazoparib)
    4ms
    A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination defective metastatic esophageal/gastroesophageal junction/proximal gastric adenocarcinoma. (PubMed, Front Oncol)
    The most common adverse events seen were anemia, fatigue, and thrombocytopenia. In patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option.
    P2 data • Journal • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ARID1A (AT-rich interaction domain 1A) • PALB2 (Partner and localizer of BRCA2) • 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) • PARP2 (Poly(ADP-Ribose) Polymerase 2)
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    FANCA deletion
    |
    Zejula (niraparib)
    4ms
    Immunome profiling in prostate cancer: a guide for clinicians. (PubMed, Front Immunol)
    Thus, it is essential to obtain more information about tumor immune cells that infiltrate these tumors, and on their plasticity and interactions, in order to better understand the underlying biology to allow development of new therapeutic strategies. This review analyzes: 1) How interactions among immune cell populations and other cells infiltrating the tumor stroma can modulate the progression of PC, 2) How the standard therapies to treat PC (such as androgen deprivation therapy, new androgen-directed hormone therapy or chemotherapy) may influence the dynamic changes of the immunome and 3) What are the limitations in characterizing the immune landscape of the host´s response to tumors.
    Review • Journal
    |
    MSI (Microsatellite instability) • CDK12 (Cyclin dependent kinase 12)
    4ms
    The CDK12-BRCA1 signaling axis mediates dinaciclib-associated radiosensitivity through p53-mediated cellular senescence. (PubMed, Mol Oncol)
    In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12-BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.
    Journal • BRCA Biomarker
    |
    TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • CDK12 (Cyclin dependent kinase 12)
    |
    BRCA1 expression
    |
    dinaciclib (MK-7965)
    4ms
    PEPN2112: Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors (clinicaltrials.gov)
    P1/2, N=31, Active, not recruiting, National Cancer Institute (NCI) | N=23 --> 31 | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Sep 2024
    Enrollment change • Trial completion date • Trial primary completion date
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • POLD1 (DNA Polymerase Delta 1) • FOXO1 (Forkhead box O1) • XRCC2 (X-Ray Repair Cross Complementing 2) • ATF1 (Activating Transcription Factor 1) • PAX3 (Paired Box 3)
    |
    elimusertib (BAY 1895344)
    5ms
    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
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    TP53 (Tumor protein P53) • CDK12 (Cyclin dependent kinase 12) • SPOP (Speckle Type BTB/POZ Protein) • CHEK1 (Checkpoint kinase 1)
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    TP53 mutation • CDK12 mutation
    5ms
    Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system. (PubMed, Cell Death Differ)
    Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.
    Review • Journal
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    5ms
    Circulating Tumor DNA (ctDNA) Testing in TALAPRO-2 Complements Tumor Testing to Gain a Greater Understanding of the Metastatic Castration-Resistant Prostate Cancer (mCRPC) Mutational Landscape (AMP 2024)
    Introduction: TALAPRO-2 (NCT03395197) demonstrated that first-line talazoparib + enzalutamide significantly improved radiographic progression-free survival versus placebo + enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). These results are supportive of the ability of F1LCDx to sensitively detect alterations in HRR genes, and the likely overall modest impact of CHiP in calling HRR gene alteration status in this study. These results support the complementary benefits of ctDNA testing to tumor tissue testing in assessing current disease alteration status, particularly AR.
    PARP Biomarker • BRCA Biomarker • Circulating tumor DNA • Metastases
    |
    BRCA2 (Breast cancer 2, early onset) • AR (Androgen receptor) • HRD (Homologous Recombination Deficiency) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • CDK12 (Cyclin dependent kinase 12) • ERG (ETS Transcription Factor ERG) • TMPRSS2 (Transmembrane serine protease 2)
    |
    BRCA2 mutation
    |
    FoundationOne® CDx • FoundationOne® Liquid CDx
    |
    Talzenna (talazoparib) • Xtandi (enzalutamide)
    5ms
    Point mutations (PM), gene amplifications (GA) and variants of unknown significance (VUS) detected by next-generation sequencing (NGS) in a real-world sample of metastatic breast cancer (MBC) (SABCS 2024)
    NGS of real-world patients reveals a broad spectrum of genomic abnormalities in MBC. TP53 and PIK3CA associate with TNBC and luminal MBC, respectively. Mutations in tumor suppressors are mostly distinct since there are many ways to induce loss-of-function.
    Real-world evidence • Clinical • MSi-H Biomarker • Next-generation sequencing • Real-world • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • RB1 (RB Transcriptional Corepressor 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CCND1 (Cyclin D1) • FGF19 (Fibroblast growth factor 19) • KMT2D (Lysine Methyltransferase 2D) • CDK12 (Cyclin dependent kinase 12) • CDH1 (Cadherin 1) • FGF4 (Fibroblast growth factor 4) • AURKA (Aurora kinase A) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • GNAS (GNAS Complex Locus) • CCND2 (Cyclin D2) • RAD21 (RAD21 Cohesin Complex Component) • KDM5A (Lysine Demethylase 5A) • ZNF217 (Zinc Finger Protein 217) • FGF23 (Fibroblast Growth Factor 23) • GATA3 (GATA binding protein 3) • ZNF703 (Zinc Finger Protein 703)
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    TP53 mutation • TMB-H • MSI-H/dMMR • PIK3CA mutation • HER-2 expression • PIK3CA H1047R • FGFR1 amplification • CCND1 amplification • FGF3 amplification
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    Guardant360® CDx
    5ms
    Exploratory biomarker analysis of Trastuzumab deruxtecan (T-DXd) vs Trastuzumab emtansine (T-DM1) efficacy in human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (mBC) in DESTINY-Breast03 (DB-03). (SABCS 2024)
    T‑DXd outperformed T‑DM1 regardless of HRD+/- or BRCA1/2 alt status, although HRD+ status and BRCA1/2 alt were poor prognosticators for PFS in both arms. Mutational analysis at DP will be presented.
    Clinical • BRCA Biomarker • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • 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) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)
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    HER-2 amplification • HER-2 mutation • HRD • EGFR positive
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    GuardantINFINITY™
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    Kadcyla (ado-trastuzumab emtansine) • Enhertu (fam-trastuzumab deruxtecan-nxki)
    5ms
    Genomic Landscape in Advanced Breast Cancer Across Different Genomic Ancestries (SABCS 2024)
    The distribution of genomic alterations is consistent across breast cancer subtypes, regardless of genomic ancestry. These findings highlight the critical need for equitable genomic testing access for all patient populations.
    Metastases
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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) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • CCND1 (Cyclin D1) • FGF19 (Fibroblast growth factor 19) • CDK12 (Cyclin dependent kinase 12) • CDH1 (Cadherin 1) • FGF3 (Fibroblast growth factor 3) • NOTCH2 (Notch 2) • NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • RAD21 (RAD21 Cohesin Complex Component) • GATA3 (GATA binding protein 3) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
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    HER-2 positive • HER-2 amplification • HER-2 negative
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    FoundationOne® CDx
    5ms
    Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K. (PubMed, RSC Chem Biol)
    This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • DDB1 (Damage Specific DNA Binding Protein 1)
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    dinaciclib (MK-7965)
    6ms
    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
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    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)
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    CDK12 mutation • AKT1 mutation • AR expression • SPOP mutation • TMPRSS2-ERG fusion • FOXA1 mutation
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    Prosigna™ Breast Cancer Prognostic Gene Signature Assay
    6ms
    Exploratory analyses of homologous recombination repair (HRR) gene subgroups and potential associations with secondary efficacy endpoints in the HRR-deficient population of TALAPRO-2 (TP-2) (DGHO 2024)
    Introduction: TP-2 (NCT03395197) demonstrated statistically significant improvement in rPFS with 1L talazoparib (TALA) + enzalutamide (ENZA) in patients (pts) with mCRPC with and without HRR gene alterations (HRRm; prospectively determined). Broad differential efficacy benefit was evident for TALA+ENZA vs PBO+ENZA across multiple molecular subgroups and was most pronounced for the BRCA1 - PALB2 - BRCA2 axis and CDK12.
    Clinical • PARP Biomarker • BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset)
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    BRCA2 mutation
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    FoundationOne® CDx • FoundationOne® Liquid CDx
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    Talzenna (talazoparib) • Xtandi (enzalutamide)
    6ms
    Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader. (PubMed, J Med Chem)
    Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CRBN (Cereblon) • CDK13 (Cyclin Dependent Kinase 13)