Rigosertib, a Pan RAS Inhibitor, Decreases Mouse and Human Myeloma Cell Growth in Preclinical Models

Introduction Multiple myeloma (MM) is a B cell cancer mainly characterized by proliferation of malignant plasma cells in the bone marrow, presence of a monoclonal serum immunoglobulin, and occurrence of osteolytic lesions. RAS genes encode a family of small GTPase proteins ubiquitously expressed in all cell lineages and organs that transmit signals for cell growth, differentiation, and survival. Mutations in RAS genes often lead to constitutively activated RAS signaling, resulting in cancer. Various RAS mutations have been described in myeloma patients. RAS mutations are rarely found in pre-malignant stages as MGUS (monoclonal gammopathy of undetermined significance). These findings suggest that RAS mutations may play an important role in malignant transformation of MM. Rigosertib (ON 01910.Na) is an inhibitor of RAS-related signaling pathways associated with cancer cell division, growth, and survival. Rigosertib binds directly to the RAS-binding domain in RAS effector proteins resulting in disruption of RAS/effector interactions and inhibition of multiple RAS-driven signaling pathways. Clinical trials with rigosertib have been conducted in MDS and solid tumors, but the effect of rigosertib in MM has not yet been fully characterized. Methods Various mouse/human MM cell lines (5TGM1, KMS28, RPMI8226, JJN3, OPM2) were tested for their growth with treatment of rigosertib at different concentrations (1, 10, 50, 100, 500 nM) for 4 days. For a mouse MM model study, 0.5e6 Luciferase infected 5TGM1 cells were injected via tail vein into C57BL6/KaLwRij mouse. Rigosertib (100 mg/kg QD) was administrated via intraperitoneal injection from 14 days post-transplantation. The MM growths were weekly monitored by in vivo IVIS imaging after luciferin (Luciferase substrate) injection. Results All cells (5TGM1, KMS28, RPMI8226, JJN3, OPM2) tested showed growth inhibition with rigosertib in a dose-dependent manner. MM progression assessed by in vivo imaging was found to be significantly suppressed by rigosertib treatment as shown in Figure. Furthermore, a survival analysis demonstrated a positive trend towards increased life expectancy with rigosertib treatment (Median survival; control (35 days) vs treated (44.5 days)). Conclusion Our results demonstrate that rigosertib suppresses MM growth in both human/mouse cell lines and a mouse MM model and suggest additional exploration of rigosertib alone or in combination with other MM treatments. Disclosures Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Hoffman: Onconova: Employment. Fruchtman: Onconova: Employment.