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Targeted Cancer Therapies

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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.

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Prostate cancer cells with CDK12 mutations are more sensitive to PARP inhibitors (PARPi). Rucaparib showed efficacy in preclinical models and clinical trials, suggesting PARPi monotherapy for specific CDK12-mutated prostate cancers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase (CDK), CDK12, is frequently altered in various cancers.
  • A specific subtype of prostate cancer exhibits loss-of-function mutations in CDK12, associated with aggressive disease.
  • Understanding CDK12's role is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the impact of CDK12 mutations on prostate cancer sensitivity to PARP inhibitors (PARPi).
  • To evaluate potential therapeutic strategies targeting CDK12-mutated prostate cancer.
  • To assess the efficacy of rucaparib in preclinical models and clinical settings.

Main Methods:

  • Generated isogenic prostate cancer models using CRISPR/Cas9 to inactivate CDK12.
  • Performed a chemical library screen of FDA-approved drugs.
  • Inhibited cyclin K and CDK13 to assess effects on PARPi sensitivity.
  • Utilized cell lines with CDK12 truncation and kinase domain mutations.
  • Treated mice bearing CDK12-mutant prostate tumors with rucaparib.
  • Evaluated PSA responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial.

Main Results:

  • CDK12-deficient cancer cells demonstrated increased sensitivity to PARPi.
  • Inhibition of cyclin K, but not CDK13, conferred PARPi sensitivity and impaired homologous recombination.
  • CDK12 truncation mutants were sensitive to PARPi, while kinase domain mutants showed intermediate sensitivity.
  • Rucaparib treatment suppressed tumor growth in mice with CDK12-mutated prostate tumors.
  • 55% of patients with biallelic CDK12 mutations experienced PSA reductions when treated with rucaparib.

Conclusions:

  • PARPi sensitivity in prostate cancer is contingent upon the specific type and zygosity of CDK12 mutations.
  • PARPi monotherapy may represent a viable treatment option for patients with prostate cancer harboring biallelic inactivating CDK12 alterations.