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PMID: 25504439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer.

Oncotarget ·Vol. 6 ·No. 2 ·2015-01-20 ·Pages 969-78

Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ, Kwong A, Tsumura A, Murphy R, Rappersberger K, Ortiz-Urda S

Abstract

Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects Cell Line, Tumor Cell Proliferation/drug effects Cell Survival/drug effects Drug Synergism GTP Phosphohydrolases/genetics,metabolism Humans Immunoblotting MAP Kinase Signaling System/drug effects Membrane Proteins/genetics,metabolism Metformin/pharmacology Mice, Nude Mutation Neoplasms/drug therapy,genetics,pathology Phosphatidylinositol 3-Kinases/metabolism Proto-Oncogene Proteins c-akt/metabolism Pyridones/pharmacology Pyrimidinones/pharmacology TOR Serine-Threonine Kinases/metabolism Tumor Burden/drug effects Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents Membrane Proteins Pyridones Pyrimidinones trametinib Metformin Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases GTP Phosphohydrolases NRAS protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Vujic Igor
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA. | Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
Sanlorenzo Martina
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA. | Department of Medical Sciences, Section of Dermatology, University of Turin, Italy.
Posch Christian
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA. | Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
Esteve-Puig Rosaura
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
Yen Adam J
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
Kwong Andrew
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
Tsumura Aaron
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
Murphy Ryan
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
Rappersberger Klemens
Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
Ortiz-Urda Susana
University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.2824
Published
2015-01-20
Pages
969-78
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4359268
Subset
IM
Grants
NCI NIH HHS · K08 CA155035 · United States
NCI NIH HHS · K08CA155035 · United States
External Links
PubMed source DOI: 10.18632/oncotarget.2824 PMC Full Text View journal details
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