PUBLICATION
Harnessing autophagy to overcome MEK-inhibitor induced resistance in metastatic melanoma
- Authors
- Verykiou, S., Alexander, M., Edwards, N., Plummer, R., Chaudhry, B., Lovat, P.E., Hill, D.S.
- ID
- ZDB-PUB-181020-31
- Date
- 2018
- Source
- The British journal of dermatology 180(2): 346-356 (Journal)
- Registered Authors
- Chaudhry, Bill
- Keywords
- MEK, THC, Autophagy, CD271, PIK-III, cannabinoid, drug-resistance, invasion, melanoma, metastasis, trametinib, vsp34, zebrafish xenograft
- MeSH Terms
-
- Animals
- Apoptosis/drug effects
- Apoptosis/immunology
- Autophagy/drug effects*
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/metabolism
- Cell Line, Tumor
- Cell Survival/drug effects
- Cell Survival/immunology
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/immunology*
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Melanoma/drug therapy*
- Melanoma/immunology
- Melanoma/pathology
- Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/prevention & control
- Nerve Tissue Proteins/analysis
- Nerve Tissue Proteins/metabolism
- Nevus/immunology
- Nevus/pathology
- Protein Kinase Inhibitors/pharmacology*
- Protein Kinase Inhibitors/therapeutic use
- Pyridones/pharmacology
- Pyridones/therapeutic use
- Pyrimidinones/pharmacology
- Pyrimidinones/therapeutic use
- RNA-Binding Proteins/analysis
- RNA-Binding Proteins/metabolism
- Receptors, Nerve Growth Factor/analysis
- Receptors, Nerve Growth Factor/metabolism
- Skin/immunology
- Skin/pathology
- Skin Neoplasms/drug therapy*
- Skin Neoplasms/immunology
- Skin Neoplasms/pathology
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 30339727 Full text @ Br. J. Dermatol.
Citation
Verykiou, S., Alexander, M., Edwards, N., Plummer, R., Chaudhry, B., Lovat, P.E., Hill, D.S. (2018) Harnessing autophagy to overcome MEK-inhibitor induced resistance in metastatic melanoma. The British journal of dermatology. 180(2):346-356.
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 Δ9-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. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping