Abstract
MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.
Highlights
Melanoma represents one of the most aggressive skin cancers with a significantly increased incidence in recent decades [1,2,3]
In order to identify miRNAs potentially involved in BRAF inhibitor resistance, we analyzed the miRNAome of melanoma cell lines sensitive to the BRAF inhibitor dabrafenib and their resistant counterparts
We investigated whether replacement or inhibition of miR-181a/b could affect the proliferation of two melanoma cell lines sensitive (A375, M14) or resistant to BRAF
Summary
Melanoma represents one of the most aggressive skin cancers with a significantly increased incidence in recent decades [1,2,3]. Current therapeutic strategies include surgical intervention, chemotherapy, targeted- and immune-therapies. In the last few years, molecular targeted- and immuno-therapies have provided marked improvements in terms of patient survival [4]. The BRAF and MEK inhibitors currently in use, such as dabrafenib, vemurafenib and trametinib, showed encouraging response rates but their efficacy is limited by mechanisms of intrinsic or acquired resistance, frequently occurring in melanoma [5]. The introduction of immune-therapies and their combination with BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) has provided significant and more durable clinical response but the majority of patients do not respond to immunotherapy or inevitably develop resistance to drugs after a period of treatment [5,6,7]
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