Abstract 3201: Rigosertib, a Ras mimetic, inhibits melanoma cell viability and synergizes with anti-PD1 to promote anti-tumor immune responses

Activating mutations in BRAF or NRAS are present in 40% and 21% of melanoma patients, respectively, leading to enhanced cell survival and proliferation. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways and interfere with CRAF interaction with PLK1 and consequently its centrosomal localization. Here, we demonstrate that RGS inhibits the cell viability at µM levels of human (including A375/SKMel2/SKMel5/HS294T) and murine (including B16F10 and YUMM2.1/3.3/4.1/5.2) melanoma cell lines with a variety of somatic mutational backgrounds. We discovered that RGS treatment immediately ( 50% inhibition of tumor volume and tumor weight, was well tolerated in mice. RGS-treated tumors exhibited an inflammatory tumor microenvironment (TME) with enrichment of dendritic cells and CD45-MHCII+ cells, elevation in frequency and activation of both CD4+ and CD8+ T cells and NK cells, but a decrease in the level of tumor-infiltrating macrophages. Of note, treatment with RGS plus αPD-1 checkpoint blockade synergistically inhibited tumor growth by ~70%. The RGS + αPD-1 combination treatment, but not the monotherapies, reduced the frequency of exhausted PD-L1+LAG3+TIM3+ CD8+ T cells at the tumor sites, as well as in the tumor-draining lymph nodes. Conclusion: These results suggest that RGS, which is a Ras mimetic, may be used in combination with anti-PD-1 immunotherapies to enhance anti-tumor immunity and optimize the treatment of melanoma. This combination therapy warrants a clinical study. The authors sincerely thank Onconova Therapeutics, Newtown, PA 18940 for kindly supplying Rigosertib for this work. Citation Format: Chi Yan, Premkumar E. Reddy, Ann Richmond. Rigosertib, a Ras mimetic, inhibits melanoma cell viability and synergizes with anti-PD1 to promote anti-tumor immune responses [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 3201.