miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma

Abstract

Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naïve human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses. Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. .

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…A recent study confirmed that overexpression of let-7b and let-7c increased the sensitivity to chemotherapeutic treatment in melanoma [130]. MiR-204 and miR-211 play a role for targeted therapy of melanoma as they can contribute to the resistance of melanoma cells to treatment with the BRAF inhibitor Vemurafenib [326]. Furthermore, a successful Phase I study applied siRNAs against the immunoproteasome, which modifies antigen processing by the proteasome in dendritic cells, thus improving recognition of tumor cells and enhancing the T-cell response against the cancer cells [327].…”

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma

“…Finally, MIR211 expression increases in melanomas treated with the BRAF inhibitor vemurafenib and may contribute to vemurafenib resistance (27,28,43). MIR211 levels were similarly increased in A375 cells treated with vemurafenib ( Fig.…”

“…Recent studies suggest that: (i) MIR211 is transported via melanosomes to the tumor microenvironment to activate MAPK signaling and thus to promote melanoma growth (11); (ii) MIR211 expression and the melanin biosynthetic pathways are induced by vemurafenib (a BRAF inhibitor) treatment and to contribute to vemurafenib resistance (27); and (iii) MIR211 contributes to BRAF inhibitor resistance in melanoma via MAPK signaling (28). Therefore, although MIR211 clearly participates in melanomagenesis, there is considerable complexity (tumor-promoter or suppressor) in its mechanisms of action that requires further clarification.…”

TEsmall identifies small RNAs associated with targeted inhibitor resistance in melanoma

“…Reassuringly, the expression alterations of miR-204 and miR-211 seen in our data were also seen in an alternative melanoma derived cell line A375 in Díaz-Martínez et al following induction of BRAF inhibitor resistance. 28 Upon further investigation into individual RNA species from different subtypes for follow up, we encountered an interesting and novel 21 nucleotide sRNA associated with the sixth intron in the vimentin gene (VIM) (Fig. 4B).…”