INHIBITORS OF ROCK KINASES INDUCE MULTIPLE MITOTIC DEFECTS AND SYNTHETIC LETHALITY IN BRCA2-DEFICIENT CELLS

SEBASTIÁN OMAR SIRI; MARES AHLERS CANDELARIA; VANESA GOTTIFREDI

Mendoza

Congreso; Sociedad Argentina de Investigacion en bioquimica y biologia molecular; 2022

SAIB

COMUNICACION ORAL Hereditary breast and ovarian cancer is an autosomal dominant diseaseprimarily caused by mutations in thebreast cancer susceptibility genes BRCA1and BRCA2. BRCA1 and BRCA2 are DNArepair genes and their protein products regulatehomologous recombination (HR),a repair pathway that processes highly toxic DNAdouble-strand breaks (DSBs).BRCA2-deficient cancer cells are highly sensitiveto poly-ADP-ribose polymeraseinhibitors (PARPi) due to the trapping of PARP onDNA. The persistence of thoseadducts augments double strand break formationwhis are selectively toxic inBRCA2-deficient cells. Thus, it is broadly assumedthat DNA damage is aprerequisite for BRCA2 synthetic lethality (SL).Challenging such a notion, herewe show that inhibiting ROCK kinases in BRCA2deficient cells triggers SLindependently from acute replication stress. Such SLis preceded by enhancedM-phase defects such as anaphase bridges, and abnormalmitotic figures, whichwere associated with multipolar spindles, supernumerarycentrosomes andmultinucleation. SL in BRCA2 deficient cells was also triggeredby inhibitingCitron Rho-interacting kinase, another enzyme which, similarly toROCK kinases,regulates cytokinesis. The SL by ROCK and Citron Kinase suggestthatBRCA2-deficient cells are sensitive to M phase inhibitors. Supportingsuchhypothesis, we identified four other druggable protein targets with afunctionin  phase and whose inhibition alsogenerates SL in a BRCA2deficient context. Further supporting the link betweenM phase and the killingof BRCA2-deficient cells, the prevention of mitoticentry by Early mitoticinhibitor 1 (EMI1) depletion promoted survival of BRCA2deficient cells treatedwith inhibitors of ROCK kinases. These results suggestthat BRCA2 deficientcells are addicted to proteins that control the M phase, revealing a potentialtherapeuticapproach to kill BRCA2-deficient tumors independently from PARPi