DEVELOPMENT OF ISOGENIC CELLULAR MODELS TO VALIDATE SL INDUCERS IN BRCA1- DEFICIENT TUMOR CELLS

PANSA MF; VILLAFAÑEZ F; GUANTAY ML; LLORENS MC; CASTELLARO A; ANGIOLINI V; GARCÍA IA; SORIA G; PANSA MF; VILLAFAÑEZ F; GUANTAY ML; LLORENS MC; CASTELLARO A; ANGIOLINI V; GARCÍA IA; SORIA G

Parana

Congreso; . LIV Reunión Anual Sociedad argentina de investigación en Bioquímica y Biología Molecular.; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Homologous recombination (HR) deficiency is a well-established driver of tumorigenesis, which is mediated by the aberrant activation of errorpronerepair mechanisms. This deficiency is linked to somatic or germline mutations in the BRCA genes, as well as other genes that participatedirectly or indirectly in the HR pathway. This has led to a remarkable interest in developing therapies that take advantage of this tumor feature,including the outstanding case of PARP inhibitors recently approved by the FDA.In our laboratory we have performed a phenotypic screeningusing flow cytometry to identify synthetic lethality (SL) inducers in BRCA1 and BRCA2-deficient cells. Using an open-source library of 680kinase inhibitors we identified Polo-Like Kinase 1 (PLK1) as a molecular target for the induction of synthetic lethality in BRCA1 deficient cells.In this work we focus in the development of isogenic cellular validation models that differ only in the expression levels of BRCA1, using breastand ovarian parental cell lines. To achieve this goal, we used a lentiviral system of shRNA expression to downregulate BRCA1 in T47D andSKOV3 cell lines. The stable cell lines generated were then used to validate the SL-activity of the PLK1 inhibitors identified in the screening, aswell as the activity of commercial PLK1 inhibitors that are currently in clinical trials.Conclusion: since PLK1 is a central kinase for mitoticprogression that is currently under clinical investigation, our results suggest that PLK1 inhibitors could be used to treat patients? cohortscharacterized by alterations in BRCA1 expression.