Abstract 4687: Rigosertib synergistically enhances the anticancer activity of Cisplatin in various preclinical models of upper gastrointestinal cancers

Abstract

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to overactive intrinsic mechanisms that mediate drug resistance.] Rigosertib is an investigational anticancer agent, that inhibits cellular signaling by acting as a Ras mimetic to effect the activation of multiple pathways associated with oncogenic transformation and drug resistance. Previous studies have demonstrated the inhibitory effect of rigosertib with conventional platinum based anticancer agents in various pre-clinical cancer models. We hypothesized that the novel mechanism of action of rigosertib would complement the DNA-damaging activity of Cisplatin (CDDP), the standard of care in UGC. To test this hypothesis, we investigated the potential therapeutic benefit of rigosertib alone and in combination with CDDP in P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of rigosertib treatment alone and/or in combination with CDDP on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, and expression of apoptotic markers. The MTT cell viability assay and Compusyn mediated median effect plot analysis (MEPA)(Chou and Talaly) were used to determine synergistic drug combinations of rigosertib and CDDP in AGS and FLO-1 UGC cells, respectively. Results: The cell viability data and MEPA indicated that rigosertib and CDDP show optimal synergistic anticancer activity in both AGS and FLO-1 UGC cells at a ratio of 1:10, respectively. The clonogenic cell survival assay data showed that in comparison to treatment with Rigosertib (AGS: 100nM; FLO-1: 50nM) or CDDP (AGS: 1000nM; FLO-1: 500nM) alone, the combination treatment at a ratio of 1:10 significantly increased (p<0.05) inhibition of cellular survival in AGS and FLO-1 UGC cell lines. The Combination Index of 0.5 suggests a strong synergism between the two drugs. Similarly, the western blot data after treatment with Rigosertib (100nM) and/or CDDP (1000nM) for 24h induced higher levels of P53/P73, P21, and cleaved PARP with Rigosertib (100nM) and CDDP (1000nM) combination treatment in UGC cells. Conclusions: Our in vitro data indicate that rigosertib, as a single agent, is an effective therapeutic strategy for inducing apoptosis in UGC cells Additionally, rigosertib in combination with CDDP synergistically enhances the anti-tumor activity of CDDP against UGC cells. The observed synergism can translate into lower drug toxicity as significant anticancer activity can be achieved with much lower doses of rigosertib and CDDP when used in combination. Citation Format: Priya Pancholi, Tanmay Dichwalkar, Samhita Bapat, V. J. Rajadhyaksha, Benjamin S. Hoffman, Manoj Maniar, Vikas Sehdev. Rigosertib synergistically enhances the anticancer activity of Cisplatin in various preclinical models of upper gastrointestinal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4687.