Polo-like Kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction

CARBAJOSA, SOFIA*; PANSA, MARÍA FLORENCIA*; PAVIOLO, NATALIA; CASTELLARO, ANDRÉS ; ANDINO, DIEGO ; NIGRA, AYELEN D. ; GARCÍA, IRIS ALEJANDRA; RACCA, ANA C. ; RODRIGUEZ-BERDINI, LUCÍA; ANGIOLINI, VIRGINIA; GUANTAY, LAURA; VILLAFAÑEZ, FLORENCIA; FEDERICO, BELÉN ; RODRÍGUEZ-BAILI, MARÍA CELESTE ; CAPUTTO, BEATRIZ LEONOR ; DREWES, GERARD ; MADAUSS, KEVIN P ; GLOGER, ISRAEL ; FERNANDEZ, ELMER ; GIL, GERMAN A ; BOCCO, JOSE LUIS; GOTTIFREDI, VANESA; SORIA, GASTÓN

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2019

1078-0432

URPOSE:BRCA1 and BRCA2-deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds.EXPERIMENTAL DESIGN:We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1 and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dual-tumor xenograft model that allowed the confirmation of SL-induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on the TCGA breast cancer database.RESULTS:The screening of a kinase inhibitors library revealed that Polo-like Kinase 1 (PLK1) inhibition triggers strong SL-induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP i