Abstract Cyclin-dependent kinase 12 (CDK12), a transcription-associated cyclin-dependent kinase (tCDK) is a tumor suppressor in prostate cancer, with biallelic loss observed in ∼1% of newly diagnosed and ∼5% of castration-resistant prostate cancer (CRPC) cases. CDK12-lost tumors are aggressive and are associated with poorer survival and rapid progression to castration resistance. CDK12 functions are essential for cell viability, limiting the mechanistic studies of its loss-of -function. In tumors, its loss is characterized by unique genomic features, notably large tandem duplications on a largely diploid background. As a tCDK, CDK12 phosphorylates RNA polymerase II and regulates transcriptional elongation and processivity. Genetic depletion or inhibition of CDK12 causes aberrant splicing, premature polyadenylation, and transcriptional termination, particularly affecting genes in the homologous recombination (HR) pathway. These defects provided a rationale for therapies such as PARP inhibitors or immune checkpoint blockade, but clinical trials have largely failed. Thus, we hypothesized that tumor cells evolve compensatory mechanisms to sustain CDK12 loss, possibly by engaging another tCDK. To better recapitulate the chronic effects of CDK12 loss observed in tumors, we utilized patient-derived organoid (PDO) models with established CDK12 loss for our studies. Using these models, we evaluated the growth-inhibitory response of CDK12-deficient PDOs to selective inhibitors targeting various transcription-associated CDKs. Notably, we found that all the CDK12-lost PDOs (n=4) were exceptionally sensitive to THZ531, an inhibitor targeting CDK12 and CDK13 (a paralog of CDK12). Next, we analyzed the global transcriptional/co-transcriptional processes in CDK12-lost and CDK12-intact models at baseline and following treatment with THZ531. Mechanistically, we found that THZ531 treatment induced increased splicing errors in CDK12-deficient organoids compared to CDK12-intact controls. The most frequent splicing aberrations were seen in intron retention and exon skipping. These findings indicate that CDK13 plays a compensatory role in maintaining transcriptional and splicing homeostasis in CDK12-deficient settings, and that targeting CDK13 represents a potential therapeutic strategy for this aggressive prostate cancer subtype. Citation Format: Shipra Shukla, Dana Schoeps, Nicholas Terri, Jahan Rehman, Omar Abdel-Wahab, Yu Chen. Understanding tumorigenesis and identifying therapeutic targets in CDK12-mutant prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B069.
Shukla et al. (Tue,) studied this question.