CDK12 is a cyclin-dependent kinase (CDK) that is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer (PC) characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features.
Using isogenic PC models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ~1800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on poly ADP-ribose polymerase inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine effects on PARPi sensitivity. Mice bearing control and CDK12 mutant prostate tumors were treated with rucaparib. Finally, we evaluated prostate specific antigen (PSA) responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial.
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%) PC patients with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Sep 25 [Epub ahead of print]
Jonathan Chou, Troy M Robinson, Emily A Egusa, Roshan Lodha, Meng Zhang, Michelle Badura, Mane Mikayelyan, Henry Delavan, Jason Swinderman, Chris Wilson, Jun Zhu, Rajdeep Das, Minh Nguyen, Andrea Loehr, Tony Golsorkhi, Andrew Simmons, Wassim Abida, Arul M Chinnaiyan, Michelle R Arkin, Eric J Small, David A Quigley, Lixing Yang, Minkyu Kim, Alan Ashworth, Felix Y Feng
University of California, San Francisco, San Francisco, CA, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States., University of California, San Francisco, San Francisco, United States., University of California, San Francisco, San Francisco, ca, United States., University Hospitals of Cleveland, Cleveland, OH, United States., Clovis Oncology, Inc., San Francisco, CA, United States., Clovis Oncology (United States), Boulder, United States., Clovis Oncology (United States), San Francisco, California, United States., University of Michigan-Ann Arbor, Ann Arbor, MI, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States., University of Chicago, United States., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States.