Exploiting ‘BRCAness’ in Homologous Repair Competent Tumors
Transcriptional addiction is a hallmark of cancer, and targeting cyclin-dependent kinases (CDKs) that regulate transcription is a highly attractive anti-cancer strategy.
Through an intra-programmatic small molecule drug discovery effort, the labs of Drs. Derek Duckett and Andrii Monastyrskyi developed a highly selective, dual CDK12/CDK13 small molecule inhibitor (SR-4835) with potent anti-cancer activity. This Cancer Cell (2019) manuscript, demonstrated that SR-4835 confers sensitivity to DNA-damaging agents and PARP inhibitors in both cell-based and preclinical patient-derived triple negative breast cancer xenograft models. The investigators demonstrated that CDK12 promotes the use of 3’-terminal polyadenylation site and silencing CDK12 increases the probability of intronic cleavage and polyadenylation.
CDK12/CDK13 inhibition triggered intronic polyadenylation site cleavage. Among genes preferentially disabled were large genes with multiple intronic polyadenylation sites, including genes encoding proteins that execute DNA repair. SR-4835 acted in synergy with multiple in-clinic DNA-damaging chemotherapies with remarkable activity in preclinical models.