Phenformin enhances the efficacy of ERK inhibition in NF1-mutant melanoma Journal Article

Authors: Trousil, S.; Chen, S.; Mu, C.; Shaw, F. M.; Yao, Z.; Ran, Y.; Shakuntala, T.; Merghoub, T.; Manstein, D.; Rosen, N.; Cantley, L. C.; Zippin, J. H.; Zheng, B.
Article Title: Phenformin enhances the efficacy of ERK inhibition in NF1-mutant melanoma
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. © 2017 The Authors
Journal Title: Journal of Investigative Dermatology
Volume: 137
Issue: 5
ISSN: 0022-202X
Publisher: Nature Publishing Group  
Date Published: 2017-05-01
Start Page: 1135
End Page: 1143
Language: English
DOI: 10.1016/j.jid.2017.01.013
PROVIDER: scopus
PMCID: PMC5392423
PUBMED: 28143781
Notes: Shakuntala Tiwari's first and last names are reversed on the original publication -- Article -- Export Date: 2 May 2017 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    359 Rosen
  2. Taha Merghoub
    201 Merghoub
  3. Shakuntala Tiwari
    7 Tiwari
  4. Zhan Yao
    22 Yao