Loss of the cyclin kinase inhibitor p27kip1 opens a therapeutic window by deregulating pathway choice after DNA double strand breaks

Abstract Reduced expression of the cyclin kinase inhibitor p27kip1 is found in many human tumors and correlates with inferior prognosis. We tested the importance of p27 loss for the induction of genetic instability in Notch driven cholangiocarcinoma (CCA). Specifically, we asked how loss of p27 interferes with DNA repair pathway choice i.e. non-homologous-end-joining (NHEJ) or homologous recombination (HR). We detected all hallmarks of HR, in p27 deficient cells even though these cells had not undergone DNA replication. This defect in pathway choice depends on a previously unknown interaction of p27 with the RAD17 protein. In a cholangiocarcinoma mouse model loss of p27 greatly accelerated tumor formation but also resulted in a strikingly increased sensitivity against DNA damage response (DDR) targeting agents. We find that 30% of human CCC patients cluster in a group which corresponds to the DDR sensitive phenotype we have identified. In this work we show that the cyclin kinase inhibitor p27kip1 has an essential role in regulating the DNA damage response. This new activity of p27 is necessary to suppress homologous recombination-based DNA repair during the G1 phase. These findings point to a role of DDR targeting drugs in CCA with low levels of p27.