Lookup NU author(s): Dr Stamatina Verykiou,
Dr Noel Edwards,
Professor Penny Lovat,
Dr David Hill
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: Patients with malignant melanoma often relapse following treatment with BRAF and/or MEK inhibitors (MEKi) due to development of drug resistance by melanoma subpopulations, mediated through induction of generic survival mechanisms. Objectives: The aim of this study was to establish the temporal pattern of CD271 regulation (a stem cell marker that mediates tumour aggressiveness) during development of resistance by melanoma to the MEKi trametinib, and to determine the association between development of resistance to trametinib and induction of pro-survival autophagy. Results: We show that CD271 and autophagic signalling are increased in human AJCC stage III primary melanomas compared to benign naevi. In vitro studies demonstrate MEKi of BRAF-mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271-expressing subpopulations. Trametinib-induced CD271 reduced autophagic flux leading to activation of pro-survival autophagy and development of MEKi-resistance. Treatment of CD271-expressing melanoma subpopulations with RNAi and small molecule inhibitors to CD271 reduced the development of MEKi-resistance, while clinically applicable autophagy modulatory agents including the cannabinoid D9-tetrahydrocannabinol (THC) and an inhibitor of the autophagy regulatory protein vps34 (PIK-III) reduced the survival of MEKi-resistant melanoma cells. Furthermore, combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi-resistant cells in an in vivo zebrafish xenograft. Conclusions: These results highlight a novel mechanism of MEKi-induced drug resistance and suggest that targeting autophagy may be a translatable approach to re-sensitize drug resistant melanoma cells to the cytotoxic effects of MEKi as an improved therapeutic strategy for patients with BRAF-mutant metastatic melanoma.
Author(s): Verykiou S, Alexander M, Edwards N, Plummer R, Chaudhry B, Lovat PE, Hill DS
Publication type: Article
Publication status: Published
Journal: British Journal of Dermatology
Print publication date: 01/02/2019
Online publication date: 19/10/2018
Acceptance date: 19/10/2018
Date deposited: 22/10/2018
ISSN (print): 0007-0963
ISSN (electronic): 1365-2133
Publisher: Wiley-Blackwell Publishing Ltd.
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