PARPI EFFICACY: THE RELEVANCE OF TISSUE ORIGIN, DRUG DURABILITY AND OFF-TARGETS

CASTRO, MARÍA VICTORIA; MOYANO, GINETTE; MENAY, FLORENCIA ; CAYROL, FLORENCIA; STERLE, HELENA; IGLESIAS, BRENDA; SHARMA, GEETA ; COLMANN, KEVIN; STRONACH, EUAN ; MADAUSS, KEVIN ; CREMASCHI, GRACIELA ; MANSILLA, SABRINA FLORENCIA ; GOTTIFREDI, VANESA

Rosario

Congreso; LIX Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research (SAIB); 2024

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

Synthetic lethality is a therapeutic strategy based on the combination of genetic and pharmacologicfactors that promote a selective cell death used to treat cancer. A well-known example of this is the appearance of PARP inhibitors (PARPi) to treat homologous recombination (HR) deficient cells. Nowadays, four PARPi – Olaparib, Rucaparib, Talazoparib and Niraparib – are approved by FDA to treat HR deficient tumors. However, Niraparib also showed great efficiency treating HR proficient ovarian tumors, indicating that although the four PARPi work by trapping PARP to DNA, its chemical differences affect their effectiveness. While there are limited reports including side-by-side comparison of PARPi, there is one report indicating that different cell lines from breast origin are more sensitive to niraparib than olaparib, an observation limited to cancers originated from these tissues. To extend this analysis, we performed survival experiments in presence of these PARPi using different cancer cell lines from several tissue origins and explored GDSC database to obtain data about the response of cell lines to niraparib and olaparib. With the exception of three cell lines, the fold difference (FD) in IC50 (olaparib/niraparib) was higher in breast/ovarian cancer cells - independently of their BRCA status - than in cancers from other tissue origin. Database analysis showed similar results indicating that Niraparib was more effective than olaparib on samples from breast/ovarian origin, an advantage not evident in samples from other tissue origin. One possible explanation is that these inhibitors have different durability, but we do not favour this possibility, as we did not see an improvement in the olaparib treatment when the survival protocol changed from single (previously mentioned results) to daily supply of the PARPi. Interestingly, a difference between olaparib and niraparib is their off-targets. Niraparib inhibits PARPs but also but also other enzymes including dCK, ALDH2, and Dyrk1A. Our current experiments are focus on determining the contribution of these off-targets to the cell killing power of niraparib.