Abstract
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.
Keywords:
Hippo; cholesterol; melanoma; metabolism; statin.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / enzymology
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Colorectal Neoplasms / pathology
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Drug Resistance, Neoplasm* / drug effects
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Drug Synergism
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / pathology
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Male
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Melanoma / drug therapy*
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Melanoma / enzymology
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Melanoma / pathology
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Mevalonic Acid / metabolism
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Mice, Nude
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Mitogen-Activated Protein Kinases / metabolism
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Prenylation*
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational / drug effects
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Signal Transduction / drug effects
Substances
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Protein Kinase Inhibitors
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Mitogen-Activated Protein Kinases
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Mevalonic Acid