Joint action of miR-126 and MAPK/PI3K inhibitors against metastatic melanoma.

Abstract

Emerging data support the rationale of combined therapies in advanced melanoma. Specifically, the combined use of drugs with different mechanisms of action can reduce the probability of selecting resistant clones. To identify agents active against melanoma cells, we screened a library of 349 anti-cancer compounds, currently in clinical use or trials, and selected PIK-75, an inhibitor of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, as the 'top active' drug. PIK-75 was then used alone or in combination with vemurafenib, the first BRAF inhibitor approved for patients with melanoma harboring BRAF mutations. We identified a combined dose of PIK-75 and vemurafenib that inhibited both the PI3K/AKT and mitogen-activated protein kinase pathways, thereby overcoming any compensatory activation. In view of the important tumor suppressor function induced by restoring expression of microRNA (miR)-126 in metastatic melanoma cells, we examined whether miR-126 has a synergistic role when included in a triple combination alongside PIK-75 and vemurafenib. We found that enforced expression of miR-126 (which alone can reduce tumorigenicity) significantly increased PIK-75 activity when used as either a single agent or in combination with vemurafenib. Interestingly, PIK-75 proved to be effective against early passage cell lines derived from patients' biopsies and on melanoma cell lines resistant to either vemurafenib or dabrafenib, thus suggesting that it potentially has the capability to overcome drug resistance. Finally, the synergistic role played by miR-126 in combination with vemurafenib and/or PIK-75 was demonstrated in vivo in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. These results not only show the efficacy of PIK-75 and vemurafenib co-treatment but also indicate that restoration of miR-126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.

• Authors: Francesca Pedini, Gabriele De Luca, Federica Felicetti, Rossella Puglisi, Alessandra Boe, Maria Beatrice Arasi, Federica Fratini, Gianfranco Mattia, Massimo Spada, Simona Caporali, Mauro Biffoni, Alessandro Giuliani, Alessandra Carè, Nadia Felli
• Journal: Molecular oncology (Mol Oncol) Vol. 13 Issue 9 Pg. 1836-1854 (09 2019) ISSN: 1878-0261 [Electronic] United States
• PMID: 31115969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Hydrazones
• MIRN126 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• PIK 75
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Neoplasm
• Sulfonamides
• Vemurafenib
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, genetics, metabolism)
• Female
• Humans
• Hydrazones (pharmacology)
• MAP Kinase Signaling System (drug effects, genetics)
• Melanoma (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Metastasis
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors (pharmacology)
• RNA, Neoplasm (genetics, metabolism)
• Sulfonamides (pharmacology)
• Vemurafenib (pharmacology)