Evasion mechanisms to Igf1r inhibition in rhabdomyosarcoma.

Abstract

Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance.

• Authors: Jinu Abraham, Suresh I Prajapati, Koichi Nishijo, Beverly S Schaffer, Eri Taniguchi, Aoife Kilcoyne, Amanda T McCleish, Laura D Nelon, Francis G Giles, Argiris Efstratiadis, Robin D LeGallo, Brent M Nowak, Brian P Rubin, Suman Malempati, Charles Keller
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 4 Pg. 697-707 (Apr 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21447712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NVP-AEW541
• Pyrimidines
• Pyrroles
• Quinazolines
• Lapatinib
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Receptor, IGF Type 1

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Child
• Chorioallantoic Membrane (drug effects, pathology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Embryo, Mammalian (drug effects, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Lapatinib
• Mice
• Phosphorylation (drug effects)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Quail
• Quinazolines (pharmacology)
• RNA Interference
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Rhabdomyosarcoma (genetics, metabolism, pathology)
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Young Adult