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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
    4d
    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
    |
    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    5d
    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.
    BRCA Biomarker • PARP 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 capsule)
    24d
    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)
    |
    dinaciclib (MK-7965)
    30d
    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
    1m
    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 • BRCA Biomarker • PARP Biomarker
    |
    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)
    |
    BRCA2 mutation
    |
    FoundationOne® CDx • FoundationOne® Liquid CDx
    |
    Talzenna (talazoparib) • Xtandi (enzalutamide capsule)
    1m
    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)
    1m
    CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. (PubMed, Cell Rep Med)
    Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.
    Journal • Synthetic lethality
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    TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    2ms
    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
    2ms
    Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition. (PubMed, Cell Rep Med)
    Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models.
    Journal • Synthetic lethality
    |
    CDK12 (Cyclin dependent kinase 12)
    2ms
    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
    2ms
    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)
    2ms
    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)
    2ms
    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
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    Opdivo (nivolumab) • Yervoy (ipilimumab)
    2ms
    Interaction of CDK12 with NXF1 is a new node for the linking mechanism between transcription and transportation of mRNA. (PubMed, Biochem Biophys Res Commun)
    Importantly, the expression level of NXF1 influences sensitivity to CDK12 inhibitors, which are emerging as novel anti-cancer drug candidates. This highlights the importance of considering the relationship between mRNA transcription and transport when targeting RNA transcription in cancer therapy.
    Journal
    |
    CDK12 (Cyclin dependent kinase 12) • NXF1 (Nuclear RNA Export Factor 1) • SECTM1 (Secreted and transmembrane 1)
    |
    NXF1 expression
    2ms
    Mutational spectrum of breast cancer by shallow whole-genome sequencing of cfDNA and tumor gene panel analysis. (PubMed, PLoS One)
    There was a 12.3% of concordance in deletions in the cfDNA-tumor pairs considering only the genes covered by the panel encompassing seven genes: BRCA1, CDK12, NF1, MAP2K4, NCOR1, TP53, and KEAP1 in three patients. This study shows the feasibility to complement the genomic analysis of tumor tissue biopsies to detect SCNA in BC using sWGS in cfDNA, providing a wider identification of potential therapeutic targets.
    Journal • BRCA Biomarker
    |
    TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • CDK12 (Cyclin dependent kinase 12) • NCOR1 (Nuclear Receptor Corepressor 1) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
    2ms
    Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer. (PubMed, Int J Biol Sci)
    Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A) • MRE11A (MRE11 homolog, double strand break repair nuclease)
    |
    HRD • BRCA mutation
    |
    Lynparza (olaparib)
    2ms
    An update on small molecule compounds targeting synthetic lethality for cancer therapy. (PubMed, Eur J Med Chem)
    This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.
    Review • Journal • Synthetic lethality
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    CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • RAD52 (RAD52 Homolog DNA Repair Protein)
    2ms
    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
    3ms
    IMPACT: Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations (clinicaltrials.gov)
    P2, N=56, Completed, University of Michigan Rogel Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Mar 2024
    Trial completion • Trial completion date • IO biomarker • Metastases
    |
    CDK12 (Cyclin dependent kinase 12)
    |
    Opdivo (nivolumab) • Yervoy (ipilimumab)
    3ms
    Acidity-Actuated Polymer/Calcium Phosphate Hybrid Nanomotor (PCaPmotor) for Penetrating Drug Delivery and Synergistic Anticancer Immunotherapy. (PubMed, Nano Lett)
    Consequently, the PCaP@THZ/αPD-L1 nanomotor resulted in synergistic anticancer immunotherapy in mice. This acid-actuated PCaPmotor represented a new paradigm for penetrating drug delivery.
    Journal
    |
    CDK12 (Cyclin dependent kinase 12)
    3ms
    Tracking down metabolic vulnerabilities in CDK12-mutant prostate cancer. (PubMed, Clin Transl Discov)
    No abstract available
    Journal
    |
    CDK12 (Cyclin dependent kinase 12)
    3ms
    DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes. (PubMed, JCO Precis Oncol)
    Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.
    Retrospective data • Journal • BRCA Biomarker • PARP Biomarker
    |
    HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • GEN1 (GEN1 Holliday junction 5' flap endonuclease) • RAD54L2 (RAD54 Like 2)
    3ms
    Elucidating the Selective Mechanism of Drugs Targeting Cyclin-Dependent Kinases with Integrated MetaD-US Simulation. (PubMed, J Chem Inf Model)
    The accurate calculation of binding free energy and the detailed analysis of the kinetic mechanism of the drug-target interaction using IMUS successfully elucidate the drug selectivity mechanism targeting the three CDKs, showing that the selectivity is primarily arising from differences in the stability of H-bonds within the Hinge region of the kinases and the interaction patterns during the protein-ligand recognition process. These findings also underscore the utility of IMUS in efficiently and accurately capturing drug-target interaction processes with clear mechanisms.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    3ms
    Real-world data on the prevalence of BRCA1/2 and HRR gene mutations in patients with primary and metastatic castration resistant prostate cancer. (PubMed, World J Urol)
    This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment.
    Journal • Real-world evidence • BRCA Biomarker • PARP Biomarker • Real-world • Metastases
    |
    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) • FANCA (FA Complementation Group A) • HDAC2 (Histone deacetylase 2)
    |
    Lynparza (olaparib)
    3ms
    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)
    3ms
    CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts. (PubMed, Nat Commun)
    Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced TRCs. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.
    Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CDK12 (Cyclin dependent kinase 12)
    3ms
    Avelumab and M6620 for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors (clinicaltrials.gov)
    P1/2, N=25, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Dec 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • 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)) • 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)
    |
    Bavencio (avelumab) • berzosertib (M6620)
    4ms
    A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer, Extra-Pulmonary Small Cell Neuroendocrine Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors (clinicaltrials.gov)
    P1/2, N=120, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | N=13 --> 120
    Enrollment open • Enrollment change
    |
    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) • 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)
    |
    berzosertib (M6620) • Trodelvy (sacituzumab govitecan-hziy)
    4ms
    Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex. (PubMed, Nat Commun)
    Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.
    Journal
    |
    CDK12 (Cyclin dependent kinase 12) • DDB1 (Damage Specific DNA Binding Protein 1)
    4ms
    CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma. (PubMed, Carcinogenesis)
    Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.
    Journal • Metastases
    |
    BCL2L1 (BCL2-like 1) • CDK12 (Cyclin dependent kinase 12) • BAX (BCL2-associated X protein)
    4ms
    Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies. (PubMed, bioRxiv)
    Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • CDK12 (Cyclin dependent kinase 12) • RAD51 (RAD51 Homolog A) • CDK13 (Cyclin Dependent Kinase 13)
    4ms
    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=31, Recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Aug 2026 | Trial primary completion date: May 2024 --> Aug 2026
    Trial completion date • Trial primary completion 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)
    4ms
    Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer. (PubMed, bioRxiv)
    This study introduces BSJ-5-63, a triple degrader designed to target CDK12, CDK7, and CDK9, making a significant advancement in CRPC therapy. The distinctive mechanism of BSJ-5-63 involves downregulating HRR genes and inhibiting AR signaling, thereby inducing a BRCAness state. This enhances sensitivity to PARP inhibition, effectively addressing ARSI resistance and improving the overall efficacy of treatment. The development of BSJ-5-63 represents a promising therapeutic approach, with the potential to benefit a broad spectrum of CRPC patients.
    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) • CDK7 (Cyclin Dependent Kinase 7) • CDK9 (Cyclin Dependent Kinase 9)
    4ms
    ATRIUM: A Study of ATG-018 (ATR Inhibitor) Treatment in Patients With Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov)
    P1, N=22, Terminated, Antengene Discovery Limited | N=88 --> 22 | Trial completion date: Jun 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jan 2024; Lack of efficacy of study compound
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler) • 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)) • 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)
    |
    ATG-018
    4ms
    Nivolumab + Docetaxel + ADT in mHSPC Patients With DDRD or Inflamed Tumors (clinicaltrials.gov)
    P2; Trial primary completion date: Jun 2024 --> Dec 2024
    Combination therapy • Trial primary completion date • Metastases
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    PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • 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) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • ABRAXAS1 (Abraxas 1 BRCA1 A Complex Subunit 2) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)
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    OncoPanel™ Assay
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    Opdivo (nivolumab) • docetaxel • goserelin acetate • Firmagon (degarelix) • leuprolide acetate for depot suspension
    4ms
    Genomic Alterations Correlated to Trastuzumab Resistance and Clinical Outcomes in HER2+/HR- Breast Cancers of Patients Living in Northwestern China. (PubMed, J Cancer)
    Ultimately, we identified a unique cancer-related gene mutation profile and a subset of genes associated with primary resistance to trastuzumab and RFS in patients with HER2+/HR- breast cancer in Northwest China. These findings could lay the groundwork for future studies aimed at elucidating the mechanisms of resistance to trastuzumab and improving HER2-targeted treatment strategies.
    Clinical data • Journal • BRCA Biomarker
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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) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • TOP2A (DNA topoisomerase 2-alpha) • FGFR4 (Fibroblast growth factor receptor 4) • CDK12 (Cyclin dependent kinase 12) • FAT1 (FAT atypical cadherin 1) • FANCA (FA Complementation Group A) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • STAG2 (Stromal Antigen 2) • EPAS1 (Endothelial PAS domain protein 1) • KMT2B (Lysine Methyltransferase 2B) • PKHD1 (PKHD1 Ciliary IPT Domain Containing Fibrocystin/Polyductin)
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    Herceptin (trastuzumab)
    4ms
    Impact of homologous recombination repair/BReast CAncer (BRCA) gene alterations on survival in a real-world setting of metastatic prostate cancer. (PubMed, BJU Int)
    Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.
    Journal • Real-world evidence • BRCA Biomarker • PARP Biomarker • Real-world • Metastases
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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) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A)
    5ms
    Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors. (PubMed, Curr Cancer Drug Targets)
    Specifically, it explores the recently uncovered roles of CDK12 kinases in various cellular processes, emphasizing the potential of CDK12 as a viable therapeutic target for the management of human tumors. Furthermore, this review provides an up-to-- date account of the advancements made in utilizing CDK12 in tumor therapy.
    Journal • IO biomarker
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    CDK12 (Cyclin dependent kinase 12)
    5ms
    Niraparib for the treatment of metastatic ccRCC in a patient with CDK12 and RAD51C mutations: a case report. (PubMed, Front Pharmacol)
    The patient received monotherapy with pazopanib and combination therapy with axitinib and tislelizumab, demonstrating limited efficacy. In summary, patients with ccRCC harboring HRR pathway gene mutation may potentially benefit from niraparib. This will present more options for ccRCC patients with limited response to conventional treatments.
    Journal • PARP Biomarker • PD(L)-1 Biomarker • Metastases
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    HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • RAD51C (RAD51 paralog C)
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    Tevimbra (tislelizumab-jsgr) • Zejula (niraparib) • pazopanib • Inlyta (axitinib)
    5ms
    Beyond BRCA: what does assessment of additional homologous recombination and mismatch repair genes in primary and metastatic prostatic adenocarcinoma add? (ECP 2024)
    We reported the frequency of HRD and MMR somatic mutations in a large real-world cohort of consecutive primary and metastatic PCs, providing a realistic estimate of the proportion of patients that could benefit from PARP or immune checkpoint inhibitors. Analysis of HR genes beyond BRCA1 and BRCA2 significantly increased the pool of patients that would be eligible for PARP inhibitor trials. BRCA1/BRCA2 and MMR mutations were more frequent in metastatic lesions suggesting these gene defects to be strong metastatic drivers.
    PARP Biomarker • BRCA Biomarker • IO biomarker • Mismatch repair • Metastases
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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) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • PMS2 (PMS1 protein homolog 2) • 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)
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    BRCA2 mutation • BRCA1 mutation
    |
    Oncomine™ Comprehensive Assay v3M
    5ms
    PEPN2112: Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors (clinicaltrials.gov)
    P1/2, N=23, 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
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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)
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    elimusertib (BAY 1895344)
    5ms
    Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group. (PubMed, Front Oncol)
    Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.
    Review • Journal • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
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    CCNE1 (Cyclin E1) • CDK12 (Cyclin dependent kinase 12) • AKT2 (V-akt murine thymoma viral oncogene homolog 2)