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

Autor: Svedman FC; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Oncology, Karolinska University Hospital, Stockholm, Sweden., Lohcharoenkal W; Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Bottai M; Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Brage SE; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Sonkoly E; Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden., Hansson J; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Oncology, Karolinska University Hospital, Stockholm, Sweden., Pivarcsi A; Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Eriksson H; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Nov 06; Vol. 13 (11), pp. e0206942. Date of Electronic Publication: 2018 Nov 06 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0206942
Abstrakt: Background: Mitogen 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 Methods: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.
Results: Increased 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).
Conclusions: EV 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.
Competing Interests: Johan Hansson has an advisory role in Novartis, Roche, Merck and Bristol Myers Squibb. Enikö Sonkoly has received research funding from Novartis, has an advisory role for Novartis and has been paid honoraria by Abbvie and Novartis. Funding to support research to co-authors from the following commercial sources has been received: Novartis, Roche, Merck, Abbvie and Bristol Myers Squibb. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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