Metformin and trametinib have synergistic effects on cell viability and tumor growth in<i>NRAS</i>mutant cancer

Abstract

// Igor Vujic 1,2 , Martina Sanlorenzo 1,3 , Christian Posch 1,2 , Rosaura Esteve-Puig 1 , Adam J. Yen 1 , Andrew Kwong 1 , Aaron Tsumura 1 , Ryan Murphy 1 , Klemens Rappersberger 2 and Susana Ortiz-Urda 1 1 University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA 2 Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria 3 Department of Medical Sciences, Section of Dermatology, University of Turin, Italy Correspondence: Igor Vujic, email: // Keywords : NRAS, metformin, trametinib, combination therapy Received : October 08, 2014 Accepted : November 24, 2014 Published : November 25, 2014 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&rsquo; 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.