Julieta Martino¹, Natalia S Paviolo¹, Sebastián S Siri¹, María F Pansa², Sofía Carbajosa², Cintia A Garro², Gastón Soria² , Vanesa Gottifredi¹
BRCA2 is involved in homologous recombination, a pathway that repairs DNA double strand breaks, one of the most lethal DNA lesions. Hereditary and somatic loss of function mutations in BRCA2 correlate with highly invasive breast and ovarian cancers that do not respond well to chemotherapy and have a poor prognosis. As such, there is an urgent need for alternative therapies. To find novel therapeutic targets, we screened a kinase inhibitor library and found that inhibition of a key mitotic kinase kills BRCA2 cells. This kinase regulates cytokinesis during mitosis and few data exist regarding crosstalk with DNA repair. Using a clinically approved and specific kinase inhibitor, we validated our screen in multiple BRCA2 cell lines. In BRCA2 cells, the kinase inhibitor induced mitotic defects such as multinucleation, aberrant metaphases and chromosome bridges. Abnormal mitotic figures were often accompanied by multipolar spindle poles and supernumerary centrosomes. Interestingly, S phase was largely unaffected. Additionally, siRNA downregulation of the mitotic kinase yielded the same phenotypes as the inhibitor, showing that the kinase is a bona fide target in BRCA2 cells. Altogether, our data suggest that inhibiting cytokinesis in BRCA2 cells induces mitotic abnormalities and polyploidy which are the likely cause of cell death. Intriguingly, these phenotypes are different than what is observed with PARP inhibition (i.e. replication stress) suggesting a new Achilles heel for BRCA2 cells.