Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK.
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.
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Celia J
CJ
Vogel
Marjon A
MA
Smit
Gianluca
G
Maddalo
Patricia A
PA
Possik
Rolf W
RW
Sparidans
Sjoerd H
SH
van der Burg
Els M
EM
Verdegaal
Albert J R
AJ
Heck
Ahmed A
AA
Samatar
Jos H
JH
Beijnen
A F Maarten
AF
Altelaar
Daniel S
DS
Peeper
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020543:Proteome / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D020543:Proteome; D054460:rho-Associated Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
MEK; NRAS; ROCK; melanoma; targeted therapy