BECAS
GUANTAY Maria Laura
artículos
Título:
Polo-like Kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction
Autor/es:
SOFIA CARBAJOSA; MARÍA FLORENCIA PANSA; NATALIA PAVIOLO; ANDRÉS CASTELLARO; DIEGO ANDINO; AYELÉN NIGRA; ALEJANDRA GARCÍA; ANA RACCA; LUCIA RODRIGUEZ; VIRGINIA ANGIOLINI; MARÍA LAURA GUANTAY; FLORENCIA VILLAFAÑEZ; MARÍA FEDERICO; MARÍA RODRIGUEZ-BAILI; BEATRIZ CAPUTTO; GERARD DREWES; KEVIN MADAUSS; ISRAEL GLOGER; ELMER FERNANDEZ; GERMÁN GIL; JOSÉ LUIS BOCCO; VANESA GOTTIFREDI; GASTÓN SORIA
Revista:
CLINICAL CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Año: 2019
ISSN:
1078-0432
Resumen:
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 of discovering novel druggable pathways for this type of malignancies, we developed an unbiassed phenotypic screening assay to simultaneously search for synthetic lethal (SL) interactions with BRCA1 and/or BRCA2. The screening of a 680 kinase inhibitors library revealed that PLK1 inhibition triggers strong SL-induction in BRCA1-deficient cells. Using isogenic models, we found 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, chimeric spheroids and with an innovative animal model of SL-induction. In line with these findings, retrospective analysis of the TCGA breast cancer database uncovered that tumors with low-BRCA1 expression display high-PLK1 levels, thus highlighting the therapeutic potential of PLK1 inhibition in this subset of cancer patients.