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Med. Sci. 2018, 6(1), 3; https://doi.org/10.3390/medsci6010003

A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors

1
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
2
Biomolecular Research Annex, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826-3227, USA
*
Author to whom correspondence should be addressed.
Received: 29 November 2017 / Revised: 21 December 2017 / Accepted: 28 December 2017 / Published: 5 January 2018
(This article belongs to the Special Issue Polyamine Metabolism in Disease and Polyamine-Targeted Therapies)
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Abstract

Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas. These tumors rely on both polyamine biosynthesis and an upregulated polyamine transport system (PTS) to maintain their high intracellular polyamine levels. We evaluated the effect of a novel arylpolyamine (AP) compound that is cytotoxic upon cellular entry via the increased PTS activity of melanoma cells with different BRAF mutational status. Mutant BRAF melanoma cells demonstrated greater PTS activity and increased sensitivity to AP compared to wild type BRAF (BRAFWT) melanoma cells. Treatment with an inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), further upregulated PTS activity in mutant BRAF cells and increased their sensitivity to AP. Furthermore, viability assays of 3D spheroid cultures of mutant BRAF melanoma cells demonstrated greater resistance to the BRAFi, PLX4720, compared to 2D monolayer cultures. However, co-treatment with AP restored the sensitivity of melanoma spheroids to PLX4720. These data indicate that mutant BRAF melanoma cells are more dependent on the PTS compared to BRAFWT melanoma cells, resulting in greater sensitivity to the PTS-targeted cytotoxic AP compound. View Full-Text
Keywords: polyamines; α-difluoromethylornithine; polyamine transport system; melanoma; mutant BRAF polyamines; α-difluoromethylornithine; polyamine transport system; melanoma; mutant BRAF
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Peters, M.C.; Minton, A.; Phanstiel IV, O.; Gilmour, S.K. A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors. Med. Sci. 2018, 6, 3.

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