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Pigment Cell Melanoma Res. 2019 Mar;32(2):292-302. doi: 10.1111/pcmr.12742. Epub 2018 Oct 22.

Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment-resistant melanoma, colorectal, and lung cancer.

Author information

1
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
2
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

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

PMID:
30281931
PMCID:
PMC6590911
[Available on 2020-03-01]
DOI:
10.1111/pcmr.12742

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