CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Identification of a Novel Inducer of Synthetic Lethality in a Homologous Recombination BRCA1/2 Deficient Cellular Model
Autor/es:
SORIA G.; GOTTIFREDI V.; FEDERICO M.B.; PANSA M.F.; PAVIOLO N.S. ; CAMPODÓNICO P.B; BOCCO J.L.; CARABAJOSA S.
Lugar:
Buenos Aires
Reunión:
Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017
Institución organizadora:
Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)
Resumen:
The identification of compounds with selective tumor cytotoxicity can improve anticancer therapies. A promising strategy which takes advantage of the frequent impairment of DNA repair pathways in tumor cells is synthetic lethality (SL). For example, the loss of the Homologous Recombination Repair (HRR) capacity is frequent in breast and ovarian cancer. In those patients normal cells are HRR proficient and therefore, the accumulation of HRR substrates should selectively cause cell death in HRR defective cancer cells but not normal cells. Such hypothesis has been validated using Poly(ADP-ribose) polymerase inhibitors (PARPi), therefore prompting the systematic search for better and more specific SL inducers.HRR loss is frequently triggered by defective or null expression of tumor suppressors BRCA1 and BRCA2. We designed a screening method to evaluate the specific ability of 684 kinase inhibitors to kill cancer cells with defects in BRCA1 and BRCA2 expression. Unexpectedly, the inhibition of one of those kinases caused the selective killing of BRCA2 defective cells with a much more modest effect in BRCA1 deficient cells. Such observations were validated in differentcell lines and using commercial inhibitors of the same kinase Ki), ruling out off- target effects. When treated with Ki, genomic aberrations and 53BP1 foci formation increased in BRCA2- but not BRCA1- depleted cells, suggesting that replication stress precedes cell death in Ki treated BRCA2-depleted samples. Finally, when combining sub-lethal concentrations of PARPi and Ki, SL was observed in BRCA2 (but not BRCA1) cells, suggesting that the treatments are not epistatic. Since the Ki sensitizes BRCA2-defective cells to sub-lethal doses of PARPs, the combined use of low doses of Ki and PARPi may improve the specific killing of BRCA2 defective tumor cells, sparing normal cells from unwanted collateral effects.