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

PANSA, MARÍA FLORENCIA*; ANDINO, DIEGO; DREWES, GERARD; FERNANDEZ, ELMER; SORIA, GASTÓN; CARBAJOSA, SOFIA*; CASTELLARO, ANDRÉS; GARCÍA, IRIS ALEJANDRA; GLOGER, ISRAEL; BOCCO, JOSÉ LUIS; GUANTAY, LAURA*; NIGRA, AYELEN D.; MADAUSS, KEVIN P; GIL, GERMAN A

Paris

Taller; Breast Cancer from the Clinic to Biology - International Course; 2019

Institute Curie

BRCA-deficiences are widespread drivers of human cancers that await the development of targeted therapies. To reachthis 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 phenotypeswith 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, chimericspheroids and mice xenografts.https://public.weconext.eu/institut-curie-training/breast-cancer-2019/2019-06-19/index.html