1. Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK.
- Author
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Vogel CJ, Smit MA, Maddalo G, Possik PA, Sparidans RW, van der Burg SH, Verdegaal EM, Heck AJ, Samatar AA, Beijnen JH, Altelaar AF, and Peeper DS
- Subjects
- Cell Line, Tumor, Humans, Melanoma enzymology, Mitogen-Activated Protein Kinase Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proteome metabolism, rho-Associated Kinases metabolism, Apoptosis drug effects, GTP Phosphohydrolases genetics, Melanoma pathology, Membrane Proteins genetics, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mutation genetics, rho-Associated Kinases antagonists & inhibitors
- 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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
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