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BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth.

Publication ,  Journal Article
Wang, T; Xiao, M; Ge, Y; Krepler, C; Belser, E; Lopez-Coral, A; Xu, X; Zhang, G; Azuma, R; Liu, Q; Liu, R; Li, L; Amaravadi, RK; Xu, W ...
Published in: Clin Cancer Res
April 1, 2015

PURPOSE: To investigate the roles of melanoma-associated macrophages in melanoma resistance to BRAF inhibitors (BRAFi). EXPERIMENTAL DESIGN: An in vitro macrophage and melanoma cell coculture system was used to investigate whether macrophages play a role in melanoma resistance to BRAFi. The effects of macrophages in tumor resistance were examined by proliferation assay, cell death assay, and Western blot analyses. Furthermore, two mouse preclinical models were used to validate whether targeting macrophages can increase the antitumor activity of BRAFi. Finally, the number of macrophages in melanoma tissues was examined by immunohistochemistry. RESULTS: We demonstrate that in BRAF-mutant melanomas, BRAFi paradoxically activate the mitogen-activated protein kinase (MAPK) pathway in macrophages to produce VEGF, which reactivates the MAPK pathway and stimulates cell growth in melanoma cells. Blocking the MAPK pathway or VEGF signaling then reverses macrophage-mediated resistance. Targeting macrophages increases the antitumor activity of BRAFi in mouse and human tumor models. The presence of macrophages in melanomas predicts early relapse after therapy. CONCLUSIONS: Our findings demonstrate that macrophages play a critical role in melanoma resistance to BRAFi, suggesting that targeting macrophages will benefit patients with BRAF-mutant melanoma.

Duke Scholars

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

April 1, 2015

Volume

21

Issue

7

Start / End Page

1652 / 1664

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transfection
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins B-raf
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Molecular Targeted Therapy
  • Mice, Inbred BALB C
 

Citation

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Wang, T., Xiao, M., Ge, Y., Krepler, C., Belser, E., Lopez-Coral, A., … Kaufman, R. E. (2015). BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth. Clin Cancer Res, 21(7), 1652–1664. https://doi.org/10.1158/1078-0432.CCR-14-1554
Wang, Tao, Min Xiao, Yingbin Ge, Clemens Krepler, Eric Belser, Alfonso Lopez-Coral, Xiaowei Xu, et al. “BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth.Clin Cancer Res 21, no. 7 (April 1, 2015): 1652–64. https://doi.org/10.1158/1078-0432.CCR-14-1554.
Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A, et al. BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth. Clin Cancer Res. 2015 Apr 1;21(7):1652–64.
Wang, Tao, et al. “BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth.Clin Cancer Res, vol. 21, no. 7, Apr. 2015, pp. 1652–64. Pubmed, doi:10.1158/1078-0432.CCR-14-1554.
Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A, Xu X, Zhang G, Azuma R, Liu Q, Liu R, Li L, Amaravadi RK, Xu W, Karakousis G, Gangadhar TC, Schuchter LM, Lieu M, Khare S, Halloran MB, Herlyn M, Kaufman RE. BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth. Clin Cancer Res. 2015 Apr 1;21(7):1652–1664.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

April 1, 2015

Volume

21

Issue

7

Start / End Page

1652 / 1664

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transfection
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins B-raf
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Molecular Targeted Therapy
  • Mice, Inbred BALB C