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MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines

Oncogene volume 33, pages 1850–1861 (2014)Cite this article

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Abstract

Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor-resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes.

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Acknowledgements

We thank P Sompalli and F Raman for technical assistance. We thank GlaxoSmithKline for SB590885, and Dr L Raptis (Queen’s University, Canada) for CPA-7. We also thank R Delgiacco of the Wistar Histology Facility. AV, JV, KLN and MH are members of the ITMAT–University of Pennsylvania. This work was supported by NIH grants PO1 CA114046, P01 CA025874, P30 CA010815, R01 CA047159 and CA076674, and by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).

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Authors and Affiliations

  1. Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA

    A Vultur, J Villanueva, C Krepler, G Rajan, Q Chen, M Xiao, L Li & M Herlyn

  2. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    P A Gimotty

  3. Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    M Wilson & K L Nathanson

  4. Division of Molecular and Cellular Biology, Imaging Facility, The Wistar Institute, Philadelphia, PA, USA

    J Hayden, F Keeney & M Herlyn

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  1. A Vultur
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Vultur, A., Villanueva, J., Krepler, C. et al. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33, 1850–1861 (2014). https://doi.org/10.1038/onc.2013.131

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