In:
Pigment Cell & Melanoma Research, Wiley, Vol. 28, No. 3 ( 2015-05), p. 307-317
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 GSK 269962A or Fasudil, in combination with either MEK inhibitor GSK 1120212 (Trametinib) or ERK inhibitor SCH 772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of Bim EL , 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.
Type of Medium:
Online Resource
ISSN:
1755-1471
,
1755-148X
DOI:
10.1111/pcmr.2015.28.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2425880-5
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