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Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma.

ABSTRACT: Resistance to RAF inhibitors such as vemurafenib and dabrafenib is a major clinical problem in the treatment of melanoma. Patients with mutant BRAF melanoma that progress on RAF inhibitors have limited treatment options, and drug removal from resistant tumors may elicit multiple effects. A frequent mechanism of resistance to RAF inhibitors is caused by expression of mutant BRAF splice variants. RAF inhibitor-resistant cell lines, generated in vivo, were tested as to whether or not mutant BRAF splice variants confer a fitness advantage in the presence of RAF inhibitor. Critically, cells expressing distinct mutant BRAF splice variants grow more efficiently in vitro and in vivo in the presence of the vemurafenib analog, PLX4720, compared with in the absence of inhibitor. PLX4720-treated BRAF splice variant-expressing cells exhibited levels of phospho-extracellular signal-regulated kinase (ERK)1/2 comparable to untreated parental cells. In addition, a reduction in phospho-ERK1/2 levels following treatment with the MEK inhibitor, trametinib (GSK1120212) phenocopied the fitness benefit provided by PLX4720. These data indicate that mutant BRAF splice variant-expressing melanoma cells are benefited by defined concentrations of RAF inhibitors.This study provides evidence that RAF inhibitor-resistant melanoma cells benefit from continued therapy.

SUBMITTER: Hartsough EJ

PROVIDER: S-EPMC4020954 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma.

Hartsough Edward J EJ Basile Kevin J KJ Aplin Andrew E AE

Molecular cancer research : MCR 20140211 5

<h4>Unlabelled</h4>Resistance to RAF inhibitors such as vemurafenib and dabrafenib is a major clinical problem in the treatment of melanoma. Patients with mutant BRAF melanoma that progress on RAF inhibitors have limited treatment options, and drug removal from resistant tumors may elicit multiple effects. A frequent mechanism of resistance to RAF inhibitors is caused by expression of mutant BRAF splice variants. RAF inhibitor-resistant cell lines, generated in vivo, were tested as to whether or ...[more]

PMID: 24520098

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Project description:BackgroundBRAF(V600E)-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAF(V600E) melanoma can be increased by its combination with BRAF-I.MethodsBRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF(V600E) metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05.ResultsThe IFNAR1 level was statistically significantly (P < .001) lower in BRAF(V600E) primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination.ConclusionsThe described results provide a strong rationale for the clinical trials implemented in BRAF(V600E) melanoma patients with BRAF-I and IFNα combination.

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Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma.

Publications

Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma.

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