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    DRUG CLASS:

    CDK12 inhibitor

    Related drugs:
    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
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
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    CDK12 mutation
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    Rubraca (rucaparib)
    2ms
    A Modular Phase 1/2 Study with CT7439 in Participants with Solid Malignancies (clinicaltrials.gov)
    P1/2, N=50, Recruiting, Carrick Therapeutics Limited
    New P1/2 trial • Combination therapy
    5ms
    Analysis of Breast Cancer Brain Metastases Reveals an Enrichment of Cyclin-Dependent Kinase 12 Structural Rearrangements in Human Epidermal Growth Factor Receptor 2-Positive Disease. (PubMed, JCO Precis Oncol)
    The most common structural rearrangements involve CDK12 with the higher prevalence in HER2-positive BCBMs. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BCBMs.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12)
    6ms
    Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer. (PubMed, Clin Transl Med)
    CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.
    Journal • PARP Biomarker
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    CDK12 (Cyclin dependent kinase 12) • ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4)
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    IACS-010759
    8ms
    Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects. (PubMed, Int J Biol Sci)
    Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
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    CDK2 overexpression
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    cisplatin
    9ms
    CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer. (PubMed, Pharmacol Res)
    Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition...Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.
    Journal • PD(L)-1 Biomarker • IO biomarker
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    CD8 (cluster of differentiation 8) • ATG7 (Autophagy Related 7)
    11ms
    The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. (PubMed, Cell Death Discov)
    Docking studies and structure-activity relationship analyses of SR-4835 revealed the importance of the benzimidazole side-chain in molecular glue activity. Together, our results indicate that SR-4835 acts as a molecular glue that recruits the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex to target cyclin K for degradation.
    Journal
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    DDB1 (Damage Specific DNA Binding Protein 1)
    1year
    Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release. (PubMed, Nucleic Acids Res)
    In summary, stimulation of Pol II pause release at the signal-responsive genes underlies the functional dependence of CDK12-inhibited cancer cells on P-TEFb. Our study establishes the mechanistic underpinning for combinatorial targeting of CDK12 with either P-TEFb or the induced oncogenic pathways in cancer.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
    1year
    Computational studies to explore inhibitors against the cyclin-dependent kinase 12/13 enzyme: an insilco pharmacophore modeling, molecular docking and dynamics approach. (PubMed, J Biomol Struct Dyn)
    Based on the cut-off criteria of free energy calculations, one common hit was selected as the dual CDK12/13 inhibitor. The outcome concluded that the hit with ID CNP0386383 possesses drug-like properties, displays crucial interaction in the binding pocket, and shows stable dynamic behaviour and higher binding energy than the experimentally reported inhibitor of both CDK12 and CDK13 enzymes.Communicated by Ramaswamy H. Sarma.
    Journal
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    CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    1year
    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
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    CDK12 (Cyclin dependent kinase 12) • TBK1 (TANK Binding Kinase 1)
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    CDK12 mutation
    1year
    MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma. (PubMed, J Exp Clin Cancer Res)
    Our study demonstrates that CDK12/13 activity represents an exploitable vulnerability in MYC-high Group 3 MB and may pave the ground for new therapeutic approaches for this high-risk brain tumor.
    Journal
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    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    1year
    Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer. (PubMed, Eur J Med Chem)
    Meanwhile, compound 12e showed favorable synergistic anti-tumor efficacy in cells and xenografts by inhibiting DNA damage repair, promoting cell cycle arrest and apoptosis. Taken together, we successfully synthesized the first effective CDK12-PARP1 dual inhibitor, which is expected to be an attractive therapeutic strategy for TNBC.
    Journal • Synthetic lethality
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    CDK12 (Cyclin dependent kinase 12)
    over1year
    Synthesis of Novel Dual Target Inhibitors of CDK12 and PARP1 and Their Antitumor Activities in HER2-Positive Breast Cancers. (PubMed, ACS Omega)
    Most synthesized compounds with various alcohols were more effective at killing tumor cells than olaparib (ola), especially in HER2-positive cancer cells. Among them, compound 9 showed potent inhibitory effects on PARP1 enzymatic activity and the PAR protein level; moreover, the expression of CDK12 was inhibited by compound 9. Overall, compound 9 exhibited a significant antitumor effect by inhibiting DNA damage repair in tumors.
    Journal • PARP Biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12)
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    HER-2 positive
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    Lynparza (olaparib)
    over1year
    Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids. (PubMed, J Exp Clin Cancer Res)
    CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.
    Journal
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    EGFR (Epidermal growth factor receptor) • CDK12 (Cyclin dependent kinase 12) • CDK13 (Cyclin Dependent Kinase 13)
    over1year
    Novel CDK12/13 Inhibitors AU-15506 and AU-16770 Are Potent Anti-Cancer Agents in EGFR Mutant Lung Adenocarcinoma with and without Osimertinib Resistance. (PubMed, Cancers (Basel))
    Interestingly, only the CDK12/13 inhibitor in combination with osimertinib, although not as monotherapy, suppresses the growth of resistant tumors in xenograft models in vivo. Taken together, the results of this study suggest that inhibition of CDK12/13 in combination with osimertinib has the potential to overcome osimertinib resistance in EGFR mutant lung adenocarcinoma patients.
    Journal
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    EGFR (Epidermal growth factor receptor) • CDK12 (Cyclin dependent kinase 12)
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    EGFR mutation
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    Tagrisso (osimertinib)
    over1year
    CDK12 Promotes the Proliferation, Migration, and Angiogenesis of Gastric Carcinoma via Activating the PI3K/AKT/mTOR Signaling Pathway. (PubMed, Appl Biochem Biotechnol)
    Further, we used LY294002 (10 μM) to treat GC cells to verify whether CDK12 regulates GC progression by activating the PI3K/AKT/mTOR pathway...Taken together, CDK12 promotes the proliferation, migration, and angiogenesis of GC by activating the PI3K/AKT/mTOR pathway. It may be a novel target for GC treatment.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
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    CDK2 overexpression
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    LY294002
    over1year
    Development, validation, and evaluation of a deep learning model to screen cyclin-dependent kinase 12 inhibitors in cancers. (PubMed, Eur J Med Chem)
    Additionally, we disclose five novel CDK12 inhibitors. These results may accelerate the discovery of novel chemical-class drugs for cancer treatment.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • CDK12 (Cyclin dependent kinase 12)
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    HER-2 positive • HER-2 amplification • CDK12 amplification
    over1year
    Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer (AACR 2023)
    Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer.
    BRCA Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
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    CDK12 mutation • BRCA1 expression
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    ISM6466A
    over1year
    Prognostic and clinicopathological value of CDK12 mutation in prostate cancer: a meta-analysis. (PubMed, Expert Rev Anticancer Ther)
    This meta-analysis indicates that patients with CDK12 mutation have poor prognosis in PCa. CDK12 may be used as a biomarker for molecular subtype and a potential therapeutic target of PCa.
    Retrospective data • Journal
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    CDK12 (Cyclin dependent kinase 12)
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    CDK12 mutation
    2years
    CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma. (PubMed, Nat Commun)
    Conversely, our results show that CDK12 inhibition promotes the expression of short genes with few exons, including many growth-promoting genes regulated by the AP-1 and NF-κB transcription factors. Inhibition of these pathways strongly synergize with CDK12 inhibitors to suppress melanoma growth, suggesting promising drug combinations for more effective melanoma treatment.
    Journal • Synthetic lethality
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    BRAF (B-raf proto-oncogene) • CDK12 (Cyclin dependent kinase 12)
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    BRAF mutation
    2years
    CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer. (PubMed, Clin Transl Med)
    Our data highlight the potential of CDK12 and SE-associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.
    Journal
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    BCL2L1 (BCL2-like 1) • CDK12 (Cyclin dependent kinase 12)
    2years
    Characterizing cyclin-dependent kinase 12(CDK12)-altered aggressive prostate cancer: a twelve-case series. (PubMed, Int J Clin Oncol)
    This is the first Japanese prostate cancer case series with CDK12 alterations. CDK12-altered prostate cancer is a heterogeneous disease, and accumulating cases with detailed information leads to precision oncology.
    Journal
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    BRCA2 (Breast cancer 2, early onset) • RB1 (RB Transcriptional Corepressor 1) • CDK12 (Cyclin dependent kinase 12)
    2years
    Dual inhibition of CDK12/CDK13 targets both tumor and immune cells in ovarian cancer. (PubMed, Cancer Res)
    Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
    2years
    CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer. (PubMed, Proc Natl Acad Sci U S A)
    Here, we demonstrate that pharmacological inhibition or genetic inactivation of CDK12 induces AR gene intronic (intron 3) polyadenylation (IPA) usage, AR-V expression, and PCa cell resistance to the antiandrogen enzalutamide (ENZ)...Our findings identify CYCLIN K down-regulation as a key driver of IPA usage, hormonal therapy-induced AR-V expression, and castration resistance in PCa. These results suggest that hormonal therapy-induced AR-V expression and therapy resistance are vulnerable to PARP inhibitor treatment.
    Journal • BRCA Biomarker • PARP Biomarker
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    AR (Androgen receptor) • HRD (Homologous Recombination Deficiency) • CAST (Calpastatin)
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    Xtandi (enzalutamide capsule)
    2years
    Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers. (PubMed, Pharmaceuticals (Basel))
    In addition, 30d exhibited a synergy with trastuzumab in the both cells, suggesting that our inhibitors could be applied to alleviate trastuzumab-resistance of HER2+ breast cancers and escalate the efficacy of trastuzumab as well. Our study may provide insight into developing a novel therapy for HER2+ breast cancers.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2)
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    HER-2 positive • HER-2 amplification
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    Herceptin (trastuzumab)
    2years
    CDK12 loss leads to replication stress and sensitivity to combinations of the ATR inhibitor camonsertib (RP-3500) with PARP inhibitors (AACR-NCI-EORTC 2022)
    Conclusions The work reports on novel evidence supporting the hypothesis that CDK12 LOF does not lead to HRD, but rather causes aberrant DNA replication origin licensing. Our findings suggest that CDK12 biallelic LOF mutations may result in a therapeutic vulnerability to ATRi/PARPi, potentially leading to a new therapeutic approach to tumors with CDK12 LOF.
    PARP Biomarker
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    CDK12 (Cyclin dependent kinase 12) • CDT1 (Chromatin Licensing And DNA Replication Factor 1)
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    camonsertib (RP-3500)
    2years
    Current progress and novel strategies that target CDK12 for drug discovery. (PubMed, Eur J Med Chem)
    Also, the drug combination strategy of CDK12 small molecule inhibitors were studied. This review discusses the latest studies on CDK12 inhibitors and analyzes their structure-activity relationships, shedding light on their further development.
    Review • Journal
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    CDK12 (Cyclin dependent kinase 12)
    over2years
    Stable CDK12 Knock-Out Ovarian Cancer Cells Do Not Show Increased Sensitivity to Cisplatin and PARP Inhibitor Treatment. (PubMed, Front Oncol)
    We found partial down-regulation of the expression of DNA repair genes at the mRNA level and, among the down-regulated genes, an enrichment in the G2/M checkpoint genes. Although the biological features of CDK12 KO cells are compatible with the function of CDK12, contrary to some reports, we could not find any difference in the sensitivity to cisplatin and olaparib between wild-type and CDK12 KO cells.
    Journal • PARP Biomarker
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    CDK12 (Cyclin dependent kinase 12)
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    Lynparza (olaparib) • cisplatin
    over2years
    CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer. (PubMed, Nat Commun)
    In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.
    Journal
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    CDK12 (Cyclin dependent kinase 12)
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    HR negative • CDK2 overexpression
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    methotrexate
    over2years
    PATIENT-DERIVED PANCREATIC CANCER ORGANOIDS FOR MODELING DRUG RESPONSE IRRESPECTIVE OF BRCA PHENOTYPE: ONE STEP CLOSER TO TAILORED TREATMENT IN PANCREATIC CANCER? (DDW 2022)
    We evaluated PDOs sensitivity to carboplatin, PARPi olaparib, CDK12/CDK13i SR-4835, and the combination of olaparib with SR-4835. PDOs profiling may predict treatment responses in patients with PDAC and provide a rationale for prioritizing therapeutic regimens. Furthermore, a synergistic therapeutic effect between olaparib and SR-4835 seems to be present, which, if confirmed and tolerated, could extend the opportunity of targeted therapy to a greater group of patients, by extending eligibility for PARPi irrespective of BRCA germline mutation status.
    Clinical • BRCA Biomarker • PARP Biomarker
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    CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset)
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    CDK12 mutation • BRCA mutation
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    Lynparza (olaparib) • carboplatin
    over2years
    Expanding the use of targeted therapy for urothelial bladder cancer (UBC): Non-FGFR3 receptor tyrosine kinase (RTK) gene rearrangements (ReAr) and fusions (fus) (AUA 2022)
    Source of Funding : Foundation Medicine Introduction : After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC...Conclusions : At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors (CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes.
    Tumor mutational burden • PD(L)-1 Biomarker • PARP Biomarker • IO biomarker
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    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR3 (Fibroblast growth factor receptor 3) • FGFR1 (Fibroblast growth factor receptor 1) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • CDK12 (Cyclin dependent kinase 12) • FUS (FUS RNA Binding Protein)
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    PD-L1 expression • FGFR3 fusion
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    PD-L1 IHC 22C3 pharmDx
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    Balversa (erdafitinib)
    over2years
    Novel Cyclin-Dependent Kinase 12 (CDK12) and Protein Kinase D1 (PrKD1) Interaction in Castration Resistant Prostate Cancer Cell Lines (AUA 2022)
    We confirmed this finding by treating C4-2-PrKD1 cells with MG-132, a 26 S proteasome inhibitor, and repeating the experiment...Conclusions : Our study demonstrates that CDK12 degradation might be mediated by PrKD1 phosphorylation at s681 and/or s685. Because PrKD1 and CKD12 are dysregulated across cancers, the results herein presented have potential implications for the treatment of not only prostate cancer but also other human malignancies.
    Preclinical
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    CDK12 (Cyclin dependent kinase 12) • PRKD1 (Protein Kinase D1)
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    MG132
    over2years
    Molecular profiles and circulating tumor-DNA detected in Chinese early stage breast cancer. (PubMed, Gland Surg)
    However, patients positive for ctDNA had a higher TMB than those negative for ctDNA when grouped according to the median TMB (1.92 mut/Mb; 85.7% vs. 38.5%; P=0.043). This study described that genomic characteristics of Chinese early stage breast cancer, and the results showed that TMB was related to the detection of ctDNA in postoperative blood.
    Journal • Tumor Mutational Burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker • Circulating tumor DNA
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    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • TYK2 (Tyrosine Kinase 2)
    |
    HER-2 positive • TP53 mutation • TMB-H • HER-2 amplification • PIK3CA mutation • HER-2 mutation • CDK12 mutation
    over2years
    Signaling of cyclin-dependent kinase 12 (CDK12) in prostate cancer cell lines (AACR 2022)
    We confirmed this finding by treating C4-2-PrKD1 cells with MG-132, a 26 S proteasome inhibitor, and repeating the experiment...Our study demonstrates that CDK12 degradation might be mediated by PrKD1 phosphorylation at s681 and/or s685. Because PrKD1 and CKD12 are dysregulated across cancers, the results herein presented have potential implications for the treatment of not only prostate cancer but also other human malignancies.
    Preclinical
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    CDK12 (Cyclin dependent kinase 12) • PRKD1 (Protein Kinase D1)
    |
    MG132
    almost3years
    CDK12 activates MYC to repress miR-28-5p/EZH2 and amplifies tonic BCR signaling to promote the development of diffuse large B-cell lymphoma. (PubMed, Cancer Gene Ther)
    In addition, CDK12 knockdown could inhibit DLBCL tumor growth in the mice model. CDK12 activated MYC to repress miR-28-5p/EZH2 and amplified tonic BCR signaling to promote the development of DLBCL, which might provide potential therapeutic targets for future therapeutic intervention in DLBCL.
    Journal
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CDK12 (Cyclin dependent kinase 12)
    |
    MYC expression