A SURVIVAL SCREEN TARGETING THE HUMAN KINOME REVEALS SYNTHETIC LETHAL INTERACTIONS WITH THERAPEUTIC POTENTIAL FOR BRCA-DEFICIENT CANCER CELLS

GASTÓN SORIA

Paraná

Congreso; 54th Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

BRCA1 and BRCA2 are well-established drivers of human cancer, playing major roles in the onset of breast and ovarian hereditary cancers. With the aim ofdiscovering novel druggable pathways for this type of malignancies, our lab developed an unbiassed phenotypic screening assay to simultaneously search forsynthetic lethal (SL) interactions with BRCA1 and/or BRCA2. The screening of a 680 kinase inhibitors library revealed unexcepted relationships that wereselectively related to BRCA1 or BRCA2. In this conference, I will present findings showing that Polo-like Kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Using isogenic models, we show that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes,which correlate with reduced clonogenic potential. The penetrance of PLK1/BRCA1 SL-interaction was validated using multiple cellular models, chimericspheroids and with an innovative animal model of SL-induction. In line with these findings, retrospective analysis of the TCGA breast cancer database uncovers that tumors with low-BRCA1 expression display high-PLK1 levels, thus highlighting the therapeutic potential of PLK1 inhibition in this subset of cancer patients.