Rigosertib, a potential RAS-targeted agent, induces CD40 expression on melanoma cells to enhance response to immune checkpoint inhibitors

ABSTRACT: Immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma. However, ICB fails in many patients and has dangerous side effects. Rigosertib (RGS), a non-ATP-competitive small molecule RAS mimetic, has the potential to block oncogenic RAS-RAF-MEK-ERK and/or PI3K-AKT-mTOR signaling pathways. RGS treatment (300mg/kg) of melanoma tumor-bearing mice is well tolerated and results in ~50% inhibition of tumor growth as monotherapy and ~70% inhibition in combination with ICB. RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells, followed by immunogenic cell death, leading to an inflamed tumor microenvironment with enrichment of dendritic cells and activated CD8+ T cells. Highlights • RGS impairs melanoma tumor growth via direct killing and immunogenic cell death that promotes an inflamed tumor microenvironment. • RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells. • Combining RGS with αPD1+αCTLA4 improves tumor response. • Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor. Significance: A high CD40 expression level correlates with CD80, ICOS-L, beneficial type I T cell responses, and better survival in melanoma patients (cBioPortal database). Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor (DepMap and Oncomine databases), and RGS induces CD40 expression in melanoma tumor cells. Our preclinical data support the therapeutic use of RGS plus αPD1+αCTLA4 in RAS/RAF/MEK and/or PI3K pathway-activated melanoma tumors and point to the need for clinical trials to determine the clinical benefit of RGS plus ICB for metastatic melanoma patients who do not respond to ICB alone.

ORGANISM(S): Mus musculus

PROVIDER: GSE149737 | GEO | 2021/06/15

REPOSITORIES: GEO