Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK |
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| Authors: | Celia J Vogel Marjon A Smit Gianluca Maddalo Patricia A Possik Rolf W Sparidans Sjoerd H van der Burg Els M Verdegaal Albert J R Heck Ahmed A Samatar Jos H Beijnen A F Maarten Altelaar Daniel S Peeper |
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| Institution: | 1. Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;2. Biomolecular Mass Spectrometry & Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands;3. Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden;4. Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;5. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands;6. Netherlands Proteomics Centre, Utrecht, The Netherlands;7. TheraMet Biosciences, Princeton Junction, NJ, USA;8. Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands |
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| Abstract: | No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL, PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma. |
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| Keywords: |
NRAS
melanoma
ROCK
MEK
targeted therapy |
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