M-CSF as a therapeutic target in BRAF V600E melanoma resistant to BRAF inhibitors

• Published in: British journal of cancer 2022-10, Vol.127 (6), p.1142
• Main Authors: Barceló, C, Sisó, P, de la Rosa, I, Megino-Luque, C, Navaridas, R, Maiques, O, Urdanibia, I, Eritja, N, Soria, X, Potrony, M, Calbet-Llopart, N, Puig, S, Matías-Guiu, X, Martí, R M, Macià, A
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Indoles - pharmacology; Indoles - therapeutic use; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - pharmacology; Macrophage Colony-Stimulating Factor - therapeutic use; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mice; Mice, SCID; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Sulfonamides - pharmacology; Vemurafenib - pharmacology; Vemurafenib - therapeutic use
• ISSN: 1532-1827

Disseminated BRAF melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAF -mutant melanoma patients. BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAF metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.