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Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer
Author(s) -
Theodosakis Nicholas,
Langdon Casey G.,
Micevic Goran,
Krykbaeva Irina,
Means Robert E.,
Stern David F.,
Bosenberg Marcus W.
Publication year - 2019
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12742
Subject(s) - vemurafenib , mapk/erk pathway , selumetinib , simvastatin , medicine , cancer research , blockade , melanoma , pharmacology , in vivo , colorectal cancer , targeted therapy , kinase , cancer , metastatic melanoma , chemistry , kras , biology , receptor , biochemistry , microbiology and biotechnology
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.