PTEN regulates IGF-1R-mediated therapy resistance in melanoma

Jun Wang, Tobias Sinnberg, Heike Niessner, Rebecca Dölker, Birgit Sauer, Wolfgang E. Kempf, Friedegund Meier, Nick Leslie, Birgit Schittek

Research output: Contribution to journalArticle

Abstract

Inhibition of the mitogen-activated protein kinase (MAPK) pathway is a major advance in the treatment of metastatic melanoma. However, its therapeutic success is limited by the rapid emergence of drug resistance. The insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in melanomas developing resistance toward the BRAF<sup>V</sup><sup>600</sup> inhibitor vemurafenib. Here, we show that hyperactivation of BRAF enhances IGF-1R expression. In addition, the phosphatase activity of PTEN as well as heterocellular contact to stromal cells increases IGF-1R expression in melanoma cells and enhances resistance to vemurafenib. Interestingly, PTEN-negative melanoma cells escape IGF-1R blockade by decreased expression of the receptor, implicating that only in melanoma patients with PTEN-positive tumors treatment with IGF-1R inhibitors would be a suitable strategy to combat therapy resistance. Our data emphasize the crosstalk and therapeutic relevance of microenvironmental and tumor cell-autonomous mechanisms in regulating IGF-1R expression and by this sensitivity toward targeted therapies.

Original languageEnglish
Pages (from-to)572-589
Number of pages18
JournalPigment Cell and Melanoma Research
Volume28
Issue number5
DOIs
Publication statusPublished - Sep 2015

Keywords

  • IGF-1R
  • Melanoma
  • PTEN
  • Therapy resistance

ASJC Scopus subject areas

  • Dermatology
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Wang, J., Sinnberg, T., Niessner, H., Dölker, R., Sauer, B., Kempf, W. E., Meier, F., Leslie, N., & Schittek, B. (2015). PTEN regulates IGF-1R-mediated therapy resistance in melanoma. Pigment Cell and Melanoma Research, 28(5), 572-589. https://doi.org/10.1111/pcmr.12390