Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma

Francesco Sabbatino, Yangyang Wang, Giosue Scognamiglio, Elvira Favoino, Steven A. Feldman, Vincenzo Villani, Keith T. Flaherty, Sjoerd Nota, Ester Simeone, Anna M. Anniciello, Giuseppe Palmieri, Stefano Pepe, Gerardo Botti, Paolo A. Ascierto, Cristina R. Ferrone, Soldano Ferrone

Research output: Contribution to journalArticle

Abstract

Background: BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN×alpha;, 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 IFN×alpha; therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanomatumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN×alpha; 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. Results: The IFNAR1 level was statistically significantly (P ×lt; .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ×le; .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 ×le; .04), pro-apoptotic (P ×le; .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ×le; .04) and MA expression as well as recognition by cognate T-cells (P ×lt; .001), of BRAF-I and IFN×alpha; combination and 2) an increased survival (P ×gt; .001) and inhibition of tumor growth of melanoma cells (P ×lt; .001) in vivo by BRAF-I and IFN×alpha; combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN×alpha; combination.

Original languageEnglish
Article numberdjv435
JournalJournal of the National Cancer Institute
Volume108
Issue number7
DOIs
Publication statusPublished - 2016

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Melanoma
Neoplasms
Cell Line
Therapeutics
Down-Regulation
Neoplasm Metastasis
T-Lymphocytes
Histocompatibility Antigens Class I
Survival
Growth
HLA Antigens
Up-Regulation
Genotype
Clinical Trials
Cytokines
Biopsy
Peptides

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sabbatino, F., Wang, Y., Scognamiglio, G., Favoino, E., Feldman, S. A., Villani, V., ... Ferrone, S. (2016). Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma. Journal of the National Cancer Institute, 108(7), [djv435]. https://doi.org/10.1093/jnci/djv435

Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma. / Sabbatino, Francesco; Wang, Yangyang; Scognamiglio, Giosue; Favoino, Elvira; Feldman, Steven A.; Villani, Vincenzo; Flaherty, Keith T.; Nota, Sjoerd; Simeone, Ester; Anniciello, Anna M.; Palmieri, Giuseppe; Pepe, Stefano; Botti, Gerardo; Ascierto, Paolo A.; Ferrone, Cristina R.; Ferrone, Soldano.

In: Journal of the National Cancer Institute, Vol. 108, No. 7, djv435, 2016.

Research output: Contribution to journalArticle

Sabbatino, F, Wang, Y, Scognamiglio, G, Favoino, E, Feldman, SA, Villani, V, Flaherty, KT, Nota, S, Simeone, E, Anniciello, AM, Palmieri, G, Pepe, S, Botti, G, Ascierto, PA, Ferrone, CR & Ferrone, S 2016, 'Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma', Journal of the National Cancer Institute, vol. 108, no. 7, djv435. https://doi.org/10.1093/jnci/djv435
Sabbatino, Francesco ; Wang, Yangyang ; Scognamiglio, Giosue ; Favoino, Elvira ; Feldman, Steven A. ; Villani, Vincenzo ; Flaherty, Keith T. ; Nota, Sjoerd ; Simeone, Ester ; Anniciello, Anna M. ; Palmieri, Giuseppe ; Pepe, Stefano ; Botti, Gerardo ; Ascierto, Paolo A. ; Ferrone, Cristina R. ; Ferrone, Soldano. / Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma. In: Journal of the National Cancer Institute. 2016 ; Vol. 108, No. 7.
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title = "Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma",
abstract = "Background: BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN×alpha;, 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 IFN×alpha; therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanomatumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN×alpha; 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. Results: The IFNAR1 level was statistically significantly (P ×lt; .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ×le; .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 ×le; .04), pro-apoptotic (P ×le; .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ×le; .04) and MA expression as well as recognition by cognate T-cells (P ×lt; .001), of BRAF-I and IFN×alpha; combination and 2) an increased survival (P ×gt; .001) and inhibition of tumor growth of melanoma cells (P ×lt; .001) in vivo by BRAF-I and IFN×alpha; combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN×alpha; combination.",
author = "Francesco Sabbatino and Yangyang Wang and Giosue Scognamiglio and Elvira Favoino and Feldman, {Steven A.} and Vincenzo Villani and Flaherty, {Keith T.} and Sjoerd Nota and Ester Simeone and Anniciello, {Anna M.} and Giuseppe Palmieri and Stefano Pepe and Gerardo Botti and Ascierto, {Paolo A.} and Ferrone, {Cristina R.} and Soldano Ferrone",
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T1 - Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma

AU - Sabbatino, Francesco

AU - Wang, Yangyang

AU - Scognamiglio, Giosue

AU - Favoino, Elvira

AU - Feldman, Steven A.

AU - Villani, Vincenzo

AU - Flaherty, Keith T.

AU - Nota, Sjoerd

AU - Simeone, Ester

AU - Anniciello, Anna M.

AU - Palmieri, Giuseppe

AU - Pepe, Stefano

AU - Botti, Gerardo

AU - Ascierto, Paolo A.

AU - Ferrone, Cristina R.

AU - Ferrone, Soldano

PY - 2016

Y1 - 2016

N2 - Background: BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN×alpha;, 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 IFN×alpha; therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanomatumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN×alpha; 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. Results: The IFNAR1 level was statistically significantly (P ×lt; .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ×le; .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 ×le; .04), pro-apoptotic (P ×le; .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ×le; .04) and MA expression as well as recognition by cognate T-cells (P ×lt; .001), of BRAF-I and IFN×alpha; combination and 2) an increased survival (P ×gt; .001) and inhibition of tumor growth of melanoma cells (P ×lt; .001) in vivo by BRAF-I and IFN×alpha; combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN×alpha; combination.

AB - Background: BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN×alpha;, 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 IFN×alpha; therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanomatumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN×alpha; 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. Results: The IFNAR1 level was statistically significantly (P ×lt; .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ×le; .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 ×le; .04), pro-apoptotic (P ×le; .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ×le; .04) and MA expression as well as recognition by cognate T-cells (P ×lt; .001), of BRAF-I and IFN×alpha; combination and 2) an increased survival (P ×gt; .001) and inhibition of tumor growth of melanoma cells (P ×lt; .001) in vivo by BRAF-I and IFN×alpha; combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN×alpha; combination.

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