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

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

Egmond aan Zee

Congreso; IABCR 2019 31st International Association for Breast Cancer Research Conference; 2019

International Association for Breast Cancer Research

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 backgrounds. The screening of a 680 kinase inhibitors library from GSK revealed that Polo-like Kinase 1 (PLK1) inhibition triggers strong SL-induction in BRCA1-deficient cells, which was comparable to the one triggered by the PARP inhibitor Olaparib. Mechanistically, we found that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication, which lead to cell death and reduced clonogenic potential. The penetrance of PLK1/BRCA1 SL-interaction was validated using multiple BRCA1-deficient and BRCA1-KO cellular models, chimeric spheroids and with an innovative animal model to asses SL-induction in vivo. Moreover, retrospective analysis of the TCGA breast cancer database revealed a remarkably high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated using BRCA1-deficient and BRCA-KO cell lines in vitro. Such unforeseen addiction of BRCA1-deficient cancers to PLK1 expression provides a new stratification strategy for patients in future clinical trials, exploiting the therapeutic potential of PLK1 inhibitors that are currently at late stages of clinical development.