Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma.

TitlePhenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsTrousil S, Chen S, Mu C, Shaw FM, Yao Z, Ran Y, Shakuntala T, Merghoub T, Manstein D, Rosen N, Cantley LC, Zippin JH, Zheng B
JournalJ Invest Dermatol
Volume137
Issue5
Pagination1135-1143
Date Published2017 May
ISSN1523-1747
KeywordsApoptosis, Cell Line, Tumor, Cell Survival, Drug Synergism, Extracellular Signal-Regulated MAP Kinases, Humans, Indazoles, Melanoma, Mutation, Neurofibromin 1, Oxygen Consumption, Phenformin, Piperazines
Abstract

Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mechanistic target of rapamycin signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate, indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma, coactivator 1-α. In contrast, cotreatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the oxygen consumption rate. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.

DOI10.1016/j.jid.2017.01.013
Alternate JournalJ. Invest. Dermatol.
PubMed ID28143781
PubMed Central IDPMC5392423
Grant ListK08 CA160657 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA166717 / CA / NCI NIH HHS / United States