Dataset Information

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

ABSTRACT:

Background

Disseminated BRAF^V600E 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.

Methods

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^V600E-mutant melanoma patients.

Results

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.

Conclusions

Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAF^V600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.

SUBMITTER: Barcelo C

PROVIDER: S-EPMC9470708 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

M-CSF as a therapeutic target in BRAF<sup>V600E</sup> melanoma resistant to BRAF inhibitors.

Barceló C C Sisó P P de la Rosa I I Megino-Luque C C Navaridas R R Maiques O O Urdanibia I I Eritja N N Soria X X Potrony M M Calbet-Llopart N N Puig S S Matías-Guiu X X Martí R M RM Macià A A

British journal of cancer 20220620 6

<h4>Background</h4>Disseminated BRAF<sup>V600E</sup> 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.<h4>Methods</h4>Conditioned media from melan ...[more]

PMID: 35725813

Similar Datasets

Project description:BackgroundMost mutations in melanoma affect one critical amino acid on BRAF gene, resulting in the V600E substitution. Patient management is often based on the use of specific inhibitors targeting this mutation.MethodsDNA and RNA mutation status was assessed in 15 melanoma cell lines by Sanger sequencing and RNA-seq. We tested the cell lines responsiveness to BRAF inhibitors (vemurafenib and PLX4720, BRAF-specific and sorafenib, BRAF non-specific). Cell proliferation was assessed by MTT colorimetric assay. BRAF V600E RNA expression was assessed by qPCR. Expression level of phosphorylated-ERK protein was assessed by Western Blotting as marker of BRAF activation.ResultsThree cell lines were discordant in the mutation detection (BRAF V600E at DNA level/Sanger sequencing and BRAF WT on RNA-seq). We initially postulated that those cell lines may express only the WT allele at the RNA level although mutated at the DNA level. A more careful analysis showed that they express low level of BRAF RNA and the expression may be in favor of the WT allele. We tested whether the discordant cell lines responded differently to BRAF-specific inhibitors. Their proliferation rate decreased after treatment with vemurafenib and PLX4720 but was not affected by sorafenib, suggesting a BRAF V600E biological behavior. Yet, responsiveness to the BRAF specific inhibitors was lower as compared to the control. Western Blot analysis revealed a decreased expression of p-ERK protein in the BRAF V600E control cell line and in the discordant cell lines upon treatment with BRAF-specific inhibitors. The discordant cell lines showed a lower responsiveness to BRAF inhibitors when compared to the BRAF V600E control cell line. The results obtained from the inhibition experiment and molecular analyses were also confirmed in three additional cell lines.ConclusionCell lines carrying V600E mutation at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

M-CSF as a therapeutic target in BRAF<sup>V600E</sup> melanoma resistant to BRAF inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

M-CSF as a therapeutic target in BRAF<sup>V600E</sup> melanoma resistant to BRAF inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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