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

SORIA G.

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2019

1078-0432

urpose: BRCA1 and BRCA2-deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds.Experimental Design: We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1 and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dual-tumor xenograft model that allowed the confirmation of SL-induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on the TCGA breast cancer database.Results: The screening of a kinase inhibitors library revealed that Polo-like Kinase 1 (PLK1) inhibition triggers strong SL-induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PA