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Neratinib, a Pan ERBB/HER Inhibitor, Restores Sensitivity of PTEN-null, BRAFV600E Melanoma to BRAF/MEK Inhibition

ABSTRACT: The A375, human BRAFV600E mutant melanoma, cell line (wildtype), two PTEN-null, BRAFV600E cell lines (KO5 and KO11), and PI3K overexpression cells (WT and PI3K H1047R mutant) were treated with small molecule inhibitors (dabrafenib, BRAF inhibitor; trametinib, MEK inhibitor alone and in combination for 0, 1 and 7 days

ORGANISM(S): Homo sapiens

PROVIDER: GSE130396 | GEO | 2019/04/27

REPOSITORIES: GEO

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Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.

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Neratinib, a Pan ERBB/HER Inhibitor, Restores Sensitivity of PTEN-null, BRAFV600E Melanoma to BRAF/MEK Inhibition

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