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

SOFIA CARBAJOSA; MARÍA FLORENCIA PANSA; MARÍA LAURA GUANTAY; ANDRÉS CASTELLARO; DIEGO ANDINO; AYELÉN NIGRA; ALEJANDRA GARCÍA; GERARD DREWES; KEVIN MADAUSS; ISRAEL GLOGER; ELMER FERNANDEZ; GERMÁN GIL; JOSÉ LUIS BOCCO; GASTÓN SORIA

París

Otro; 4th Course on Breast Cancer: from the Clinic to the Biology; 2019

Insitut Curie

BRCA-deficiences 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/BRCA1 SL-interaction was validated using several isogenic and non-isogenic cellular models, chimeric spheroids and mice xenografts.