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Hyperactivation of MEK–ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells

Oncogene volume 30, pages 366–371 (2011)Cite this article

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Abstract

Activating mutations in B-RAF and N-RAS occur in ∼60 and ∼15% of melanomas, respectively. The most common mutation in B-RAF is V600E, which activates B-RAF and the downstream MEK–ERK1/2 pathway. Thus, B-RAFV600E is a viable therapeutic target. PLX4720 is a selective inhibitor of mutant B-RAF and its analog, PLX4032, is currently undergoing clinical trials in melanoma. However, the effects of PLX4720 across the genotypic spectrum in melanoma remain unclear. Here, we describe that PLX4720 treatment rapidly induces hyperactivation of the MEK–ERK1/2 pathway in mutant N-RAS melanoma cells. Furthermore, we demonstrate that C-RAF is the major RAF isoform involved in this process. Importantly, PLX4720-induced hyperactivation of the MEK–ERK1/2 pathway promotes resistance to apoptosis in both non-invasive and invasive mutant N-RAS melanoma cells but does not enhance cell cycle properties. These findings underscore the need to genotypically stratify melanoma patients before enrollment on a mutant B-RAF inhibitor trial.

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Acknowledgements

We thank Dr Gideon Bollag (Plexxikon) for providing PLX4720, Dr Meenhard Herlyn (Wistar Institute) for cell lines and Dr Michele Weiss for comments on the manuscript. This work was supported by National Institutes of Health Grants (R01-GM067893 and R01-CA125103), and Pennsylvania Department of Health (AF0301) to AE Aplin.

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Authors and Affiliations

  1. Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    F M Kaplan, Y Shao, M M Mayberry & A E Aplin

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  1. F M Kaplan
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  2. Y Shao
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  3. M M Mayberry
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  4. A E Aplin
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Correspondence to A E Aplin.

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Kaplan, F., Shao, Y., Mayberry, M. et al. Hyperactivation of MEK–ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene 30, 366–371 (2011). https://doi.org/10.1038/onc.2010.408

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