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(V) (600) 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1111/pcmr.12390 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells.
Front Immunol
December 2024
Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg-University (JGU) Medical Center, Mainz, Germany.
Background: The insulin-like growth factor 1 receptor (IGF-1R) and the thyrotropin receptor (TSH-R) are expressed on orbital cells and thyrocytes. These receptors are targeted in autoimmune-induced thyroid eye disease (TED). Effective therapeutic treatment of TED inhibits activation of the IGF-1R/TSH-R complex.
View Article and Find Full Text PDFTargeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia.
Discov Oncol
December 2024
Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan.
Patients with chronic myeloid leukemia (CML) frequently develop resistance to tyrosine kinase inhibitors such as imatinib. In this study, we explored the role of the insulin-like growth factor 1 (IGF-1) signaling pathway in CML and imatinib resistance. An analysis of IGF-1 gene expression using public databases revealed elevated levels of insulin-like growth factor-binding proteins in patients with chronic-phase CML.
View Article and Find Full Text PDFLinsitinib Decreases Thyrotropin-Induced Thyroid Hormone Synthesis by Inhibiting Crosstalk Between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors in Human Thyrocytes and in Mice.
Thyroid
December 2024
Laboratory of Endocrinology and Receptor Biology, Bethesda, Maryland, USA.
Thyrotropin receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) have been shown to crosstalk in primary cultures of human thyrocytes (hThyros) and Graves' orbital fibroblasts. The phenomenon of TSHR/IGF-1R crosstalk has been largely studied in the pathogenesis of thyroid eye disease (TED) in human orbital fibroblasts. Here, we investigated the effects of inhibiting the IGF-1R-mediated contribution to crosstalk by linsitinib (Lins), a small-molecule IGF-1R kinase inhibitor, on TSH-induced regulation of thyroperoxidase (TPO) and thyroglobulin (TG) mRNAs and proteins in hThyros and on TPO and TG mRNAs and free thyroxine (fT4) levels in mice.
View Article and Find Full Text PDFPossible Involvement of Hippocampal miR-539-3p/Lrp6/Igf1r Axis for Diminished Working Memory in Mice Fed a Low-Carbohydrate and High-Protein Diet.
Mol Nutr Food Res
December 2024
Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University, Maebashi, Gunma, Japan.
A low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function with the decreased expression of hippocampal insulin-like growth factor-1 receptor (IGF-1R) among healthy mice. However, the precise mechanisms underlying this phenomenon remain unexplored. Eight-week-old male C57BL/6 mice were divided into the LC-HP diet-fed group (25.
View Article and Find Full Text PDFTranscriptomic profiling of thyroid eye disease orbital fat demonstrates differences in adipogenicity and IGF-1R pathway.
JCI Insight
December 2024
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Despite recent advances in the treatment of thyroid eye disease thyroid-related eye disease (TED), marked gaps remain in our understanding of the underlying molecular mechanisms, particularly concerning the insulin-like growth factor-1 receptor (IGF-1R) pathway. To dissect the pathophysiology of TED, we used single-nucleus RNA-Seq to analyze orbital fat specimens from both patients with TED and matched individuals acting as controls. The analysis demonstrated a marked increase in the proportion of fibroblasts transitioning to adipogenesis in the orbital fat of patients with TED compared with that in control patients.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!