Abstract 3026: Rigosertib (RIG) modulates MAPK and hematopoiesis signaling and synergizes Azacitidine (AZA) altering viral mimicry pathway in myelodysplastic syndrome (MDS)
Authors: Melana Stella M. , Rai Richa , Navada Shyamala C. , Odchimar-Reissig Rosalie , Demakos Erin P. , Reddy E. Premkumar , Silverman Lewis R. 
Published: August 2019

Abstract
MDS is a heterogeneous stem cell disorder characterized by hyperproliferative bone marrow (BM) and peripheral blood cytopenias involving one or more lineages. AZA, a hypomethylating agent (HMA) is considered 1st line therapy for higher-risk disease. About 50% of MDS patients (pts) respond to AZA, with a median response of 14-24 month (Silverman Cancer Med 9th ed). For pts responding to AZA, most either relapse or progress with worsening BM failure and have a median survival of 4-6 months. Both primary and secondary resistance remains a significant challenge and results in poor survival. We previously reported that RIG, a ras-mimetic identified as a novel anticancer drug, inhibits cell cycle progression, induces apoptosis and acts as a HDAC inhibitor with chromatin modifying activity. In a Phase I/II study the combination of RIG+AZA produced an 85% overall response rate in pts who were HMA naive and 62% in HMA failures (Navada EHA 2017). The ability to reverse the resistance phenotype is a novel observation with clinical implications. In this study, we investigated the effect of AZA and RIG alone or in sequential combination (RIG/AZA; AZA/RIG) (SC) on MDS-L cell line to identify the mechanism of action of the drugs. QPCR array was used to identify the differential gene expression profile. Maximum gene alteration was observed (±2 fold change) on treatment with RIG alone, AZA/RIG and RIG/AZA with differential expression of 20 (14up+6dn), 22 (16up+6dn) and 21 (16up+5dn) genes, respectively. However, AZA alone showed minimal effect with dysregulation, the expression of only 2 genes (1up+1dn). Further, gene expression with 1.5 fold change was used for biological and functional analysis. Interestingly, hematopoiesis cell lineage and JAK-STAT signaling were the pathways most affected in RIG alone, and both the SCs. MAPK signaling is impacted in cells treated with RIG alone and AZA/RIG. This suggests that RIG plays a crucial role in modulating these pathways. However, cytokine-cytokine receptor interactions were impacted only in cells treated with both SCs. RIG-I like receptor signaling was specifically observed only in RIG/AZA. This pathway along with Toll-like receptor (TLR) signaling in RIG/AZA suggests the involvement of viral mimicry. Moreover, TLR signaling dysregulation with AZA also suggests association with viral mimicry and impacts the cell cycle pathway. These results indicate that RIG either alone or in combination acts via the MAPK signaling pathway and impacts hematopoietic signaling. In contrast, AZA had no impact on these signaling pathways. This suggests that RIG in combination with AZA affects important signaling pathways impacting hematopoiesis and may explain the synergy seen in MDS pts. Further study is needed to understand the mechanism of resistance to AZA in MDS patients and identify the potential target for reversal of drug resistance.
Citation Format: Stella M. Melana, Richa Rai, Shyamala C. Navada, Rosalie Odchimar-Reissig, Erin P. Demakos, E. Premkumar Reddy, Lewis R. Silverman. Rigosertib (RIG) modulates MAPK and hematopoiesis signaling and synergizes Azacitidine (AZA) altering viral mimicry pathway in myelodysplastic syndrome (MDS) [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 3026.