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 language | English |
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Pages (from-to) | 572-589 |
Number of pages | 18 |
Journal | Pigment Cell and Melanoma Research |
Volume | 28 |
Issue number | 5 |
DOIs | |
Publication status | Published - Sept 2015 |
Keywords
- IGF-1R
- Melanoma
- PTEN
- Therapy resistance
ASJC Scopus subject areas
- Dermatology
- Oncology
- General Biochemistry,Genetics and Molecular Biology