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Proteomic analysis of secretomes from WM9/Hs294T melanoma cells resistant and non-resistant to BRAF/MEK and from their co-cultures with adipocytes

ABSTRACT: Treatment based on BRAF/MEK kinase inhibitors is currently one of the most commonly used methods in melanoma therapy. Unfortunately, in the case of advanced melanoma, patients often develop resistance to treatment at an early stage of the treatment. A thorough understanding of the causes and mechanisms may contribute to the development of new, more effective treatments. One of the ways in which treatment-resistant cells can affect other cancer cells and the tumor microenvironment is through the factors they secrete. Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor) and compare it with the secretome of non-resistant cells. Proteomic analysis, followed by gene ontology (GO) analysis, identified many differences in resistant melanoma cells' secretomes compared to controls (non-resistant) in terms of cellular compartment, molecular function, biological processes, and reactome pathways. Proteins unique to the secretomes of resistant cells were associated with, among others, integrin binding and interactions, and the extracellular matrix organization. Other interesting groups of proteins, i.e., up- or downregulated in secretomes of resistant melanoma cells vs their non-resistant variants, were directly related to cancer progression and associated with cell adhesion, actin cytoskeleton organization, matrix proteolysis, and drug resistance. Proteins included in these groups, once secreted by resistant melanoma cells, can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Aleksandra Simiczyjew

PROVIDER: MSV000099457 | MassIVE | Mon Oct 13 01:53:00 BST 2025

SECONDARY ACCESSION(S): PXD069384

REPOSITORIES: MassIVE

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Project description:The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAFV600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease through a variety of mechanisms. We previously described the creation of a panel of spontaneously BRAFi/MEKi-resistant A375 melanoma cells that displayed multiple different resistance mechanisms arising within the same parental cell population. These resistance mechanisms include (i) rearrangements in the BRAF gene resulting in truncation of the N-terminal regulatory domain or tandem duplication of the BRAF kinase domain, (ii) loss of Ras-GAP NF1, and (iii) a slower arising form of drug resistance associated with a more spread cell morphology and increased phospho-MEK S298, a characteristic of cells with increased Rac1 signaling. We provide here comprehensive gene expression profiling for this panel of cell lines. Rac1 mutation, particularly the P29S variant, is common in melanoma patients, where it is associated with BRAFi/MEKi resistance and worse clinical outcomes. Here we delineate mechanisms of Rac1-driven MAPKi-resistance and identify strategies to inhibit the growth of this class of cutaneous melanomas. We find that Rac1-driven melanomas manifest pleiotropic resistance mechanisms including (i) reduced dependence on BRAF/MEK, (ii) activation of alternative MAPK pathways utilizing Jun kinase and p38 MAP kinase, and (iii) a partial reliance on YAP/TAZ signaling. Importantly, although Rac1-driven melanoma cells display reduced dependence on BRAF/MEK, they are not completely ERK-independent. Moreover, the presence of activated Rac1 appears to create a dependency on focal adhesion kinase (FAK) signaling in undifferentiated melanoma cells. As a result, we find that, despite the pleiotropic mechanisms of Rac1-driven MAPKi resistance, combined inhibition of MEK and FAK with avutometinib plus defactinib is a promising approach for suppressing the growth of Rac1-driven cells. Thus, the avutometinib plus defactinib combination, which is currently being investigated for brain metastatic cutaneous melanoma may also have utility against Rac1-driven MAPKi-resistance in heavily pre-treated, advanced disease.

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Proteomic analysis of secretomes from WM9/Hs294T melanoma cells resistant and non-resistant to BRAF/MEK and from their co-cultures with adipocytes

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