18P - Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four consensus molecular subtypes

Abstract

Background: DNA damage response (DDR) is crucial in a variety of tumours. Colorectal cancer (CRC) shows some features of dependency upon DDR such as frequent activation of RAS-MAPK pathway, that is strongly associated with mitotic stress. Moreover, several approved chemotherapeutics in CRC are typical DNA damaging agents that require active DDR systems in cancer cells to be tolerated (e.g. irinotecan and oxaliplatin). It has been recently shown that PARP inhibitors are able to potentiate the anti-proliferative effect of irinotecan and oxaliplatin, particularly in MSI tumours. However, there is still no correlation between niraparib response and Consensus Molecular Subtypes (CMS). Methods: We analysed the sensitivity using MTT proliferation assay to the PARP-inhibitor niraparib used alone or in combination with either 5-fluorouracil (5FU), irinotecan (active metabolite SN38) or oxaliplatin in a panel of 8 KRAS (HCT15, LOVO, LS1034, SW1116, SW948, HCT116, SW480) or BRAF (WiDr) mutated CRCs, from the four CMS clusters. Combination index analysis was performed in order to evaluate the synergism between niraparib and the chemotherapeutics. Further characterization of sensitive cell lines was performed using western blot, cell cycle and apoptosis analyses. Results: Niraparib showed synergistic activity when used in combination with chemotherapeutics in most cell lines used. In particular, the combination with SN38 exhibited the strongest synergism, while synergism with 5FU was only evident in a minority of the analysed cell lines. Synergistic effect between niraparib and chemotherapy was evidenced across all the four CMS. Cell cycle and apoptosis assays revealed differences in sensitive cell lines in terms of increased induction of apoptosis. Conclusions: Combination of niraparib and chemotherapy in RAS/BRAF mutated CRC is synergistic irrespectively of CMS. SN38 is the best candidate for combination. Further analyses are needed in order to find other markers predictive of good response to PARP inhibitors and chemotherapy in this model. Legal entity responsible for the study: Department of Precision Medicine, Università della Campania Luigi Vanvitelli. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.