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M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors

C Barceló1, P Sisó1, I de la Rosa1

  • 1Oncologic Pathology Group, University of Lleida, IRBLleida, Lleida, Spain.

British Journal of Cancer
|June 20, 2022
PubMed
Abstract

Insights

Secreted Macrophage Colony-Stimulating Factor (M-CSF) drives resistance to BRAF inhibitors in metastatic melanoma. Targeting M-CSF offers a new therapeutic strategy for improving patient prognosis in BRAF-mutant melanoma.

Area of Science:

  • Oncology
  • Melanoma Research
  • Cancer Therapeutics

Background:

  • Disseminated BRAFV600E melanoma initially responds to BRAF inhibitors (BRAFi) but frequently develops resistance, leading to poor prognosis.
  • The tumor secretome significantly influences cancer progression and therapeutic outcomes.
  • Secreted Macrophage Colony-Stimulating Factor (M-CSF) is implicated in suppressing melanoma cell death and promoting tumor growth.

Purpose of the Study:

  • To investigate the role of M-CSF in the development of resistance to BRAF-targeted therapies in metastatic melanoma.
  • To analyze the contribution of M-CSF to therapeutic resistance and patient prognosis in BRAFV600E melanoma.

Main Methods:

  • Analysis of conditioned media from melanoma cells using citoarray.
  • In vitro assays assessing melanoma cell viability, migration, and invasion.
  • In vivo tumor growth assessment in xenografted SCID mice.
  • Evaluation of M-CSF plasma levels in 35 metastatic BRAFV600E-mutant melanoma patients and correlation with clinical prognosis.

Main Results:

  • The secretome of BRAFi-resistant melanoma cells is enriched with pro-tumor cytokines, including M-CSF.
  • M-CSF secretion was essential for establishing a Vemurafenib-resistant phenotype in melanoma cells.
  • Combination therapy with M-CSF monoclonal antibody (mAb), Vemurafenib, and autophagy inhibitors synergistically induced apoptosis, reduced migration, and inhibited tumor growth in resistant cells.
  • Lower plasma M-CSF levels correlated with better prognosis in metastatic melanoma patients.

Conclusions:

  • Secreted M-CSF promotes a BRAFi-resistant phenotype and is associated with a worse prognosis in BRAFV600E metastatic melanoma.
  • These findings highlight secreted M-CSF as a potential therapeutic target for overcoming BRAFi resistance in melanoma.

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