c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression

Oncogene. 2012 Apr 5;31(14):1804-16. doi: 10.1038/onc.2011.361. Epub 2011 Sep 5.

Abstract

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Progression
  • Humans
  • Matrix Metalloproteinase 1 / metabolism
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Melanoma / secondary
  • Mice
  • Neoplasm Invasiveness
  • Protein-Tyrosine Kinases / metabolism*
  • Protein-Tyrosine Kinases / pharmacology
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Pyrimidines / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Pyrimidines
  • STAT3 Transcription Factor
  • ARG tyrosine kinase
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-abl
  • Matrix Metalloproteinase 1