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

<div>AbstractPurpose:<p>The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations in <i>CDK12</i>. This subtype exhibits aggressive clinical features.</p>Experimental Design:<p>Using isogenic prostate cancer models generated by CRISPR/Cas9-mediated inactivation of <i>CDK12</i>, we conducted a chemical library screen of ∼1,800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on PARP inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine the effects on PARPi sensitivity. Mice bearing control and CDK12-mutant prostate tumors were treated with rucaparib. Finally, we evaluated PSA responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial.</p>Results:<p>Cancer cells lacking CDK12 are more sensitive to PARPi than isogenic wild-type cells, and sensitivity depends on the degree of CDK12 inhibition. Inhibiting cyclin K, but not CDK13, also led to PARPi sensitivity and suppressed homologous recombination. CDK12 truncation mutants remained sensitive to PARPi, whereas kinase domain mutants exhibited intermediate sensitivity. The PARPi rucaparib suppressed tumor growth in mice bearing CDK12-mutated tumors. Finally, 6 of 11 (55%) patients with prostate cancer with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial.</p>Conclusions:<p>In prostate cancer, sensitivity to PARPi is dependent on the specific type and zygosity of the <i>CDK12</i> mutation. PARPi monotherapy may have some activity in patients with prostate cancer with biallelic inactivating CDK12 alterations.</p></div>