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

SOFÍA CARBAJOSA; MARÍA PANSA; DIEGO ANDINO; ANDRÉS CASTELLARO; NATALIA PAVIOLO; DIEGO ANDINO; AYELEN NIGRA; IRIS GARCIA; ANA RACCA; LUCÍA RODRIGUEZ-BERDINI; FLORENCIA VILLAFAÑE; MARÍA RODRÍGUEZ-BAILI; BEATRIZ CAPUTTO,; GERARD DREWES; KEVIN MADAUSS; ISRAEL GLOGER; ELMER FERNANDEZ; GERMAN A GIL; JOSE LUIS BOCCO; VANESA GOTTIFREDI; GASTON SORIA

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2019

1078-0432

RCA1 and BRCA2 are well-established drivers of human cancer, playing major roles in the onset of breast and ovarian hereditary cancers. With the aim of discovering novel druggable pathways for this type of malignancies, we developed an unbiassed phenotypic screening assay to simultaneously search for synthetic lethal (SL) interactions with BRCA1 and/or BRCA2. The screening of a 680 kinase inhibitors library revealed that PLK1 inhibition triggers strong SL-induction in BRCA1-deficient cells. Using isogenic models, we found that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes, which correlate with reduced clonogenic potential. The penetrance of PLK1/BRCA1 SL-interaction was validated using multiple cellular models, chimeric spheroids and with an innovative animal model of SL-induction. In line with these findings, retrospective analysis of the TCGA breast cancer database uncovered that tumors with low-BRCA1 expression display high-PLK1 levels, thus highlight