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

Abstract

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[tpltrtarr] Dinaciclib is a radiosensitising agent in lung and colon cancer cell lines. [tpltrtarr]Dinaciclib promotes radiosensitivity by inhibiting CDK12 leading to a decrease in BRCA1 expression. [tpltrtarr]Lack of BRCA1 blocks homologous recombination response to DNA damage, enhancing ionising radiation-associated senescence in a p53-dependent fashion. [tpltrtarr]The combination of dinaciclib plus radiotherapy could be a novel treatment for tumours holding functional BRCA1 and p53 signalling.