Identification of a novel inducer of synthethic lethality in a homologous recombination BRCA 1/2 deficient cellular model.

PAOLA CAMPODÓNICO; NATALIA PAVIOLO; SOFÍA CARBAJOSA; MARÍA FLORENCIA PANSA; BELEN FEDERICO; JOSÉ LUIS BOCCO; VANESA GOTTIFREDI; GASTÓN SORIA

Congreso; Reunión conjunta de sociedades de biociencias; 2017

The identification of compounds with selective tumor cytotoxicitycan improve anticancer therapies. A promising strategy which takesadvantage of the frequent impairment of DNA repair pathways intumor cells is synthetic lethality (SL). For example, the loss of theHomologous Recombination Repair (HRR) capacity is frequentin breast and ovarian cancer. In those patients normal cells areHRR proficient and therefore, the accumulation of HRR substratesshould selectively cause cell death in HRR defective cancer cellsbut not normal cells. Such hypothesis has been validated usingPoly(ADP-ribose) polymerase inhibitors (PARPi), therefore promptingthe systematic search for better and more specific SL inducers.HRR loss is frequently triggered by defective or null expression oftumor suppressors BRCA1 and BRCA2. We designed a screeningmethod to evaluate the specific ability of 684 kinase inhibitors to killcancer cells with defects in BRCA1 and BRCA2 expression. Unexpectedly,the inhibition of one of those kinases caused the selectivekilling of BRCA2 defective cells with a much more modest effect inBRCA1 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 aberrationsand 53BP1 foci formation increased in BRCA2- but notBRCA1- depleted cells, suggesting that replication stress precedescell death in Ki treated BRCA2-depleted samples. Finally, whencombining sub-lethal concentrations of PARPi and Ki, SL was observedin BRCA2 (but not BRCA1) cells, suggesting that the treatmentsare not epistatic. Since the Ki sensitizes BRCA2-defectivecells to sub-lethal doses of PARPs, the combined use of low dosesof Ki and PARPi may improve the specific killing of BRCA2 defectivetumor cells, sparing normal cells from unwanted collateral effects.