Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors

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.