Cytokinesis inhibition induces synthetic lethality and mitotic abnormalities in BRCA2-deficient cell lines

SIRI, SEBASTIÁN OMAR; CARBAJOSA SOFIA ; GOTTIFREDI, VANESA; PAVIOLO, NATALIA SOLEDAD; GARRO, CINTIA ; MARTINO, JULIETA; PANSA, F MARIA ; SORIA, GASTON

Buenos Aires

Simposio; Buenos Aires Breast Cancer Symposium BA-BCS2020; 2021

BRCA2 is involved in homologous recombination, apathway that repairs DNA double strand breaks, one of themost lethal DNA lesions. Hereditary and somatic loss offunction mutations in BRCA2 correlate with highly invasivebreast and ovarian cancers that do not respond well tochemotherapy and have a poor prognosis. As such, thereis an urgent need for alternative therapies. To find noveltherapeutic targets, we screened a kinase inhibitor libraryand found that inhibition of a key mitotic kinase kills BRCA2cells. This kinase regulates cytokinesis during mitosis andfew data exist regarding crosstalk with DNA repair. Usinga clinically approved and specific kinase inhibitor, we validated our screen in multiple BRCA2 cell lines. In BRCA2cells, the kinase inhibitor induced mitotic defects such asmultinucleation, aberrant metaphases and chromosomebridges. Abnormal mitotic figures were often accompaniedby multipolar spindle poles and supernumerary centrosomes. Interestingly, S phase was largely unaffected.Additionally, siRNA downregulation of the mitotic kinaseyielded the same phenotypes as the inhibitor, showing thatthe kinase is a bona fide target in BRCA2 cells. Altogether,our data suggest that inhibiting cytokinesis in BRCA2 cellsinduces mitotic abnormalities and polyploidy which are thelikely cause of cell death. Intriguingly, these phenotypesare different than what is observed with PARP inhibition(i.e. replication stress) suggesting a new Achilles heel forBRCA2 cells.