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Harnessing autophagy to overcome MEK-inhibitor induced resistance in metastatic melanoma

Lookup NU author(s): Dr Stamatina Verykiou, Michael Alexander, Dr Noel Edwards, Professor Ruth Plummer, Dr Bill Chaudhry, Professor Penny Lovat, Dr David Hill

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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

Year: 2019

Volume: 180

Issue: 2

Pages: 346-356

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.

URL: https://doi.org/10.1111/bjd.17333

DOI: 10.1111/bjd.17333


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