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; MARÍA CELESTE RODRIGUEZ-BAILI; CAPUTTO, BEATRIZ LEONOR; DREWES, GERARD; MADAUSS, KEVIN P; GLOGER, ISRAEL; FERNANDEZ, ELMER; GIL, GERMAN A; BOCCO, JOSÉ LUIS; GOTTIFREDI, VANESA; SORIA, GASTÓN

Basel

Congreso; Basel Breast Consortium Annual Meeting 2019; 2019

http://baselbc.org/bbc-annual-meeting-2019-2/

BRCA-deficiencies are widespread drivers of human cancers that await the development of targeted therapies. To reach this aim, we developed a high-throughput phenotypic screening technology based of multiparametric flow cytometry to simultaneously search for synthetic lethal (SL) interactions in BRCA1 and BRCA2-deficient contexts.The screening of a kinase inhibitors library revealed that Polo-like Kinase 1 (PLK1) inhibition triggers strong SL-induction in BRCA1-deficient cells. We uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA SL-interaction was validated using several isogenic and non-isogenic cellular models, chimeric spheroids and mice xenografts.