PLK 1 INHIBITION AS A THERAPEUTIC APPROACH TO TARGET BRCA1-DEFICIENT CANCER CELLS BY SYNTHETIC LETHALITY

CARBAJOSA, SOFIA*; PANSA, MARÍA FLORENCIA*; GUANTAY, LAURA*; PAVIOLO, NATALIA; CASTELLARO, ANDRÉS; ANDINO, DIEGO; NIGRA, AYELEN D.; GARCÍA, IRIS ALEJANDRA; GIL, GERMAN A; BOCCO, JOSÉ LUIS; GOTTIFREDI, VANESA; SORIA, GASTÓN

Salta

Congreso; Joint LV Annual SAIB Meeting and XIV PABMB Congress; 2019

SAIB PABMB

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 usingBRCA-deficient isogenic backgrounds. To reach this goal, we developed a phenotypic screeningtechnology to simultaneously search for synthetic-lethal (SL) interactions in BRCA1 and BRCA2-deficientcontexts. The screening of a kinase inhibitors library revealed that Polo-like Kinase 1 (PLK1) inhibitiontriggers strong SL-induction in BRCA1-deficient cells. We uncovered that BRCA1 down-regulation and PLK1inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, whichseverely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL-interaction wasvalidated using several isogenic and non-isogenic cellular models, chimeric spheroids, and micexenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, aphenotype that was consistently recapitulated byinducing BRCA1 deficiency in multiple cell lines as well asin BRCA1-mutant cells. Collectively, we uncovered an unforeseen addiction of BRCA1-deficient cancercells to PLK1 expression, which provides a new mean to exploit the therapeutic potential of PLK1inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patients?cohorts.