Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase.

O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting of OGT and CDK12 is toxic to prostate cancer cells. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation and due to its essentiality in higher eukaryotes, it is not an ideal drug target. Our glycoproteomics-data revealed that short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in different models of prostate cancer. By integrating our glycoproteomics-, gene essentiality- and clinical-data from CDK12 mutant prostate cancer patients, we identify the non-essential serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12-inactivation. Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome.

Emerging frontiers in androgen receptor research for prostate Cancer: insights from the 2nd international androgen receptor Symposium.

Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26-27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.

CDK9 inhibition activates innate immune response through viral mimicry.

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition-induced cancer cell-selective anti-proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics, and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB-driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage in vitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.