Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade
Year: 2021
Type: article
Abstract: Background 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. Methods Rigosertib (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. Results RGS 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. Conclusions 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 + ICB for melanoma patients who do not respond to ICB alone. Trial registration NCT01205815 (Sept 17, 2010). Graphical abstract
Source: Molecular Cancer
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,480
Awards: G1188393146, G1221739687, G1388609297, G2006259475, Leica Bond RX, G283432789, G3152736877, New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors, G359867969, Vanderbilt Mouse Metabolic Phenotyping Center, G4424950377, G4513176822, G526617753, G5853943267, G6297262231, G6860057478, G7018334597, Investigating concurrent Ras-pathway inhibition to optimize response to anti-PD-1 therapy in NRAS-mutant melanoma, VOLT (Vanderbilt Oncology Training Program), G9000081609, G9000130502, Cancer Center Support Grant, Combining senescence-inducing and senolytic agents to improve melanoma therapy
OpenAlex ID: W3171259716