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

Oncogene volume 31, pages 1804–1816 (2012)Cite this article

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.

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Acknowledgements

We thank Patty Cross, J Anthony Brandon, Holly Bennett and Jennifer Strange for assistance with IHC, IVIS imaging, isolation of GST–STAT3 and cell sorting, respectively; John D’Orazio for primary melanocytes; Meenhard Herlyn for WM melanoma cell lines and for genotyping WM cell lines; Suyan Huang for A375; Fernando deCastro for IHC advice and Paul Manley (Novartis, Switzerland) for STI571 and nilotinib, and advice regarding their use. This work was supported by NIH/NCI grant 1R01CA116784.

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Authors and Affiliations

  1. Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, KY, USA

    S S Ganguly, L S Fiore, J T Sims, J W Friend, D Srinivasan, M A Thacker, M Novak, D M Kaetzel & R Plattner

  2. Department of Pathology, University of Kentucky School of Medicine, Lexington, KY, USA

    M L Cibull

  3. Department of Biostatistics and Markey Cancer Center, University of Kentucky School of Medicine, Lexington, KY, USA

    C Wang

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Correspondence to R Plattner.

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Dr Plattner's and Dr Kaetzel's work are supported by NIH CA116784 and CA83237, respectively. All of the other authors declare no potential conflict of interest.

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Ganguly, S., Fiore, L., Sims, J. et al. c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression. Oncogene 31, 1804–1816 (2012). https://doi.org/10.1038/onc.2011.361

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