Plk1 inhibition as a therapeutic approach to targer BRCA1-deficient cancer cells by synthetic lethality.

PANSA MF, CARBAJOSA S, GUANTAY L , PAVIOLO N , CASTELLARO A , ANDINO D4 , NIGRA A, GARCÍA IA , GIL G , BOCCO JL , GOTTIFREDI V , SORIA G

Mendoza

Congreso; LV Anual Conference. SAIB -PABMB (Sociedad argentina de investigaciones bioquímicas- Pan American Society of Biochemistry and Molecular Biology); 2019

BioCell

BRCA-deficiencies are widespread drivers of human cancers that await the development of targeted therapies. In this work, we aimed to identify novel synthetic?lethal interactions with therapeutic potential using BRCA-deficient isogenic backgrounds. To reach this goal, we developed a phenotypic screening technology 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 down-regulation 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. Moreover, bioinformatics analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells. Collectively, we uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patients? cohorts.