Crosstalk signaling in targeted melanoma therapy

Abstract

Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAFV600E/K mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche. After a certain adaptation period, this can turn out to be beneficial for tumor growth and metastasis—even in cases of good initial tumor response. This review sheds light on the biology of BRAF/MEK inhibitor-sensitive melanoma cells, which survive targeted therapy and will address the crosstalk signaling events occurring in BRAF mutant melanomas when the BRAF/MAPK pathway is fully blocked. The knowledge of these events is important for potential future drug combinations, which enhance the inhibitory effect of BRAF/MEK inhibition, particularly in patients not eligible for immune therapy.

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Acknowledgements

The author is supported by the Interdisciplinary Center for Clinical Research (University Hospital Würzburg, grant number B-323) and by the research unit FOR2314 (German Research Foundation).

I apologize to all authors whose work could not be referenced owing to space limitations.

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Correspondence to Svenja Meierjohann.

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Meierjohann, S. Crosstalk signaling in targeted melanoma therapy. Cancer Metastasis Rev 36, 23–33 (2017). https://doi.org/10.1007/s10555-017-9659-z

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Keywords

  • Melanoma therapy
  • MITF
  • WNT
  • EGFR
  • Negative feedback
  • Tumor microenvironment