Abstract DNA damage response (DDR) is crucial in a variety of tumors and several new drugs that interfere with this mechanism are already available or in advanced clinical testing. RAS-MAPK pathway activation, induced by either RAS or BRAF mutation, is a frequent feature of colorectal cancers (CRCs) and is strongly associated to mitotic stress and dependency upon DDR. Among the drugs used for CRC, oxaliplatin and irinotecan are known to induce DNA damage in form of single or double strand breaks (SSB/DSBs) and thus require active DDR systems in cancer cells to be tolerated. The poly-ADP-Ribose Polymerase (PARP) inhibitor Niraparib (MK-4827) is an FDA-approved orally bioavailable drug with strong PARP1-trapping activity, a feature ofted associated with synergism in combination with platinum salts, while synergism with other DNA damaging agents is independent of the PARP1-trapping activity. We tested the activity of niraparib used in combination with oxaliplatin or irinotecan (in the form of its active metabolite SN38) in a panel of 8 KRAS or BRAF mutated CRC cell lines (LOVO, HCT15, SW1116, LS1034, SW948, WiDr, SW480, HCT116) with different microsatellite and CIMP status. Combination index (CI) analysis was performed in order to evaluate the synergism between niraparib and the chemotherapeutics. Cell cycle distribution and apoptosis assays were performed in order to further characterize the effects of the combinations. The combination between niraparib and oxaliplatin resulted synergistic in 6 out of 8 cell lines, with strong synergism (CI < 0,5) in 2 cell lines, while the combination between niraparib and irinotecan (SN38) resulted synergistic in 7 out of 8 cell lines, with strong synergism in 5 cell lines and very strong synergism (CI < 0,1) in 3 cell lines. Interestingly, the only non-synergistic cell line to the combination with irinotecan is also non-synergistic to the combination with oxaliplatin; on the other hand, the cell lines that exhibit strong synergism to the combination with irinotecan do not present strong synergism to the combination with oxaliplatin and vice versa. Moreover, all the microsatellite instable (MSI) cell lines tested resulted synergistic for the two combinations. Finally, the synergistic combinations showed an increased induction of apoptosis and cell cycle arrest compared to non-synergistic combinations. Taken together, these data investigate the combination between the PARP inhibitor niraparib and the antiproliferative agents oxaliplatin and irinotecan in KRAS/BRAF mutated CRC cell lines, showing how MSI status predicts good synergism with the drug combinations, while MSS status is not a good predictor of synergism. Further studies are needed to identify better predictive biomarker beyond MSI status, in order to optimize the use of these combinations for future development. Citation Format: Pietro Paolo Vitiello, Davide Ciardiello, Claudia Cardone, Giulia Martini, Valentina Belli, Nunzia Matrone, Luca Poliero, Carola Borrelli, Pasquale Vitale, Nicoletta Zanaletti, Teresa Troiani, Davide Melisi, Fortunato Ciardiello, Erika Martinelli. Synergism between oxaliplatin or irinotecan with the PARP inhibitor niraparib in a preclinical model of KRAS/BRAF mutated colorectal cancer is associated with MSI status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 295.