Abstract
BackgroundWhile immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.MethodsRigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data.ResultsRGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.ConclusionsOur data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.Trial registrationNCT01205815 (Sept 17, 2010).Graphical abstract
Highlights
20% of melanoma patient tumors harbor mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), 60% have a mutually exclusive mutation to NRAS in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and 31% have mutation in the phosphoinositide 3-kinase (PI3K) pathway [1, 2]
Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + immune checkpoint blockade (ICB) for melanoma patients who do not respond to ICB alone
Rigosertib induces melanoma cell death and inhibits melanoma tumor growth in vitro and in vivo We first evaluated the cytotoxic activity of RGS in four human and six murine melanoma cell lines with diverse genetic backgrounds, including cells with NRASQ61R, BRAFmut, PTENnull, TP53null/mut and/or CDKN2Anull (Suppl.Table 1)
Summary
20% of melanoma patient tumors harbor mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), 60% have a mutually exclusive mutation to NRAS in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and 31% have mutation in the phosphoinositide 3-kinase (PI3K) pathway [1, 2]. These pathways are crucial to support melanoma cell proliferation, survival, or evasion of cell death. While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy
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