The signalling axis CDK12-BRCA1 mediates dinaciclib associated radiosensitivity through p53-mediated cellular senescence

Pan-CDK inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as monotherapy, an interesting approach could be to combine it with radiotherapy. Here we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter responses such as ATM signalling, apoptosis or cell cycle profiling after ionising radiation exposure that have been described for other CDK inhibitors. Mechanistically, inhibition of CDK12 by dinaciclib abolishes BRCA1 expression, which blocks homologous recombination (HR), leaving only the non-homologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising radiation-associated cellular senescence in a p53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report explains the molecular mechanism involved in this novel therapeutic effect of dinaciclib and provides a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour. Highlights ### Competing Interest Statement The authors have declared no competing interest. * (CDKs) : Cyclin-dependent kinases (IR) : Ionising radiation (SA-β-Gal) : Senescence-Associated β-Galactosidase (HR) : Homologous Recombination (NHEJ) : Non-Homologous End Joining (shRNA) : Short hairpin RNA (TGCA) : The Cancer Genome Atlas (S.D.) : Standard deviation (SF) : Surviving fraction (SASP) : Senescence-associated secretory phenotype (WT) : Wild type