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Publication
Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway
inhibition augments response to checkpoint blockade.
Authors Yan C, Saleh N, Yang J, Nebhan CA, Vilgelm AE, Reddy EP, Roland JT, Johnson DB,
Chen SC, Shattuck-Brandt RL, Ayers GD, Richmond A
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Molecular cancer
Year 2021
Date Published 6/1/2021
Volume : Pages 20 : 85
PubMed Reference 34092233
Abstract 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., 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., 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 aPD1?+?aCTLA4. 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., Our data
support the therapeutic use of RGS?+?aPD1?+?aCTLA4 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., NCT01205815
(Sept 17, 2010).




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