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Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells.

Abstract
Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma.
AuthorsS Martin, A M Dudek-Perić, H Maes, A D Garg, M Gabrysiak, S Demirsoy, J V Swinnen, P Agostinis
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 93 Issue 3 Pg. 290-304 (Feb 1 2015) ISSN: 1873-2968 [Electronic] England
PMID25529535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Butadienes
  • Enzyme Inhibitors
  • Indoles
  • Nitriles
  • PLX4032
  • Sulfonamides
  • U 0126
  • MAP Kinase Kinase Kinases
Topics
  • Autophagy (drug effects, physiology)
  • Butadienes (pharmacology)
  • Cell Death (drug effects, physiology)
  • Coculture Techniques
  • Drug Resistance, Neoplasm (drug effects, physiology)
  • Enzyme Inhibitors (pharmacology)
  • Humans
  • Indoles (pharmacology, therapeutic use)
  • MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
  • Melanoma (drug therapy, metabolism)
  • Nitriles (pharmacology)
  • Signal Transduction (drug effects, physiology)
  • Sulfonamides (pharmacology, therapeutic use)

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