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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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
Issue number5
Publication statusPublished - Sept 2015


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

ASJC Scopus subject areas

  • Dermatology
  • Oncology
  • General Biochemistry,Genetics and Molecular Biology


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