Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma

Abstract

BackgroundMitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.Materials and methodsEV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.ResultsIncreased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8–1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13–0.52, P <0.000061).ConclusionsEV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.

Regulation of microRNA‑497 expression in human cancer (Review)

“…Subsequently, it was demonstrated that the expression level of miR-497 increases significantly following surgical resection of the primary tumor, indicating that serum miR-497 may be used to evaluate the effect of the surgery, and even as a prognostic index of malignant astrocytoma (16). It was recently reported that miR-497 in extracellular microvesicles is a predictive biomarker of the benefits of mitogen-activated protein kinase pathway inhibitor therapy in patients with metastatic cutaneous malignant melanoma (141). In addition to the aforementioned prognostic indicators, survival analysis may also be used to reflect the prognosis of disease treatment.…”

Up‐regulation of microRNA‐574 attenuates lipopolysaccharide‐ or cecal ligation and puncture‐induced sepsis associated with acute lung injury

“…In recent years, the regulation of microRNA (miRNA) in various physiological and pathological processes has received increasing attention. 10,11 MiRNAs, which are a class of non-coding nucleotide single-stranded small-molecule RNAs, participate in various biological processes such as cell proliferation, differentiation and apoptosis. 12 In recent years, studies have found that miRNA could be used as a new biomarker in the diagnosis of sepsis.…”

<p>Circular RNA Profiling Reveals That circRNA_104433 Regulates Cell Growth by Targeting miR-497-5p in Gastric Cancer</p>

“…4,19 During therapy, elevated levels of extracellular microvesicle miR-497-5p lead to prolonged progression-free survival in metastatic cutaneous malignant melanoma. 20 According to TCGA database analysis, hsa-miR-497-5p was shown to be down-regulated in GC. Liu et al have reported that knockdown of LINC00662 reduced miR-497-5p expression and decreased GC cell proliferation, while increased the chemo-sensitivity of GC cells.…”