Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment-resistant melanoma, colorectal, and lung cancer.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/ pharmacology
Lung Neoplasms
/ drug therapy
Male
Melanoma
/ drug therapy
Mevalonic Acid
/ metabolism
Mice, Nude
Mitogen-Activated Protein Kinases
/ metabolism
Prenylation
Protein Kinase Inhibitors
/ pharmacology
Protein Processing, Post-Translational
/ drug effects
Signal Transduction
/ drug effects
Hippo
cholesterol
melanoma
metabolism
statin
Journal
Pigment cell & melanoma research
ISSN: 1755-148X
Titre abrégé: Pigment Cell Melanoma Res
Pays: England
ID NLM: 101318927
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
18
05
2018
revised:
09
09
2018
accepted:
12
09
2018
pubmed:
4
10
2018
medline:
9
8
2019
entrez:
4
10
2018
Statut:
ppublish
Résumé
This study evaluates the use of HMG-CoA reductase inhibitors, or statins, as an adjunctive to BRAF and MEK inhibition as a treatment in melanomas and other tumors with driver mutations in the MAPK pathway. Experiments used simvastatin in conjunction with vemurafenib and selumetinib in vitro and simvastatin with vemurafenib in vivo to demonstrate additional growth abrogation beyond MAPK blockade alone. Additional studies demonstrated that statin anti-tumor effects appeared to depend on inhibition of isoprenoid synthesis given rescue with add-back of downstream metabolites. Ultimately, we concluded that statins represent a possible useful adjunctive therapy in MAPK-driven tumors when given with current approved targeted therapy.
Identifiants
pubmed: 30281931
doi: 10.1111/pcmr.12742
pmc: PMC6590911
mid: NIHMS991102
doi:
Substances chimiques
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Protein Kinase Inhibitors
0
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Mevalonic Acid
S5UOB36OCZ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
292-302Subventions
Organisme : NCI NIH HHS
ID : F30 CA180591
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA128814
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196660
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007324
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA121974
Pays : United States
Informations de copyright
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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