Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

Abstract

The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.

Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib

“…In the present study, we screened the alterations in the secretome profiles of vemurafenib-sensitive vs. vemurafenib-resistant RKO colon cancer cells carrying BRAFV600E mutation. Although a similar study has already been conducted in BRAFV600E human melanoma cells [ 30 ], there are no literature data available on the secretory features concurrent with the development of resistance to BRAFV600E inhibitors in colon cancer. The methodological approach we employed here was based on combining two complementary proteomics platforms including 2-DE/MALDI TOF/TOF MS and LC-MS/MS, which ensured increased proteome coverage and bypassed the limitations inherent to each individual analytical approach.…”

β-elemene Isopropanolamine Derivative LXX-8250 Induces Apoptosis Through Impairing Autophagic Flux via PFKFB4 Repression in Melanoma Cells

“…Melanoma is the leading cause of skin cancer death worldwide. Although immunotherapies and targeted therapies show efficacy in melanoma recently, drug resistance remains an obstacle ( Kim and Cohen, 2016 ; Wang et al, 2018b ; Tabolacci et al, 2021 ). Therefore, novel approaches to melanoma treatment are needed with great urgency.…”

Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

“…Evidence is emerging for a role for chemokines as prognostic and predictive biomarkers of therapy responses; CXCL5 has been postulated as a biomarker for the response to anti-PD-1 therapy, with high baseline levels associated with the response to treatment [ 116 ], and serum CXCL8 has been shown to decrease in patients who develop good responses to immunotherapy [ 117 ]. CXCL8 has been shown in many studies to correlate with tumour burden; the levels of CXCL8 in the serum of tumour-bearing mice and humans fall following surgical excision [ 118 ], patients with brain metastasis express high levels of CXCL8 in cerebrospinal fluid [ 119 , 120 ], and CXCL8 has been shown to be higher in models of BRAF inhibitor (BRAFi)-resistant melanoma [ 121 ].…”