Journal
TRANSLATIONAL ONCOLOGY
Volume 9, Issue 6, Pages 540-547Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.tranon.2016.09.002
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Funding
- Intramural Research Program of National Institutes of Health, the National Cancer Institute
- Intramural Research Program of National Institutes of Health, Center for Cancer Research
- Conquer Cancer Foundation of ASCO Young Investigator Award - Quad W Foundation
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To determine what alternative pathways may act as mechanisms of bypass resistance to type 1 insulin-like growth factor receptor (IGF-1R) blockade in rhabdomyosarcoma (RMS), we compared expression of receptor tyrosine kinase activity in a number of IGF-1R antibody-resistant and -sensitive RMS cell lines. We found that platelet-derived growth factor receptor beta (PDGFR-beta) activity was upregulated in three xenograft-derived IGF-1R antibody-resistant cell lines that arose from a highly sensitive fusion-positive RMS cell line (Rh41). Furthermore, we identified four additional fusion-negative RMS cell lines that similarly upregulated PDGFR-beta activity when selected for IGF-1R antibody resistance in vitro. In the seven cell lines described, we observed enhanced growth inhibition when cells were treated with dual IGF-1R and PDGFR-beta inhibition in vitro. In vivo studies have confirmed the enhanced effect of targeting IGF-1R and PDGFR-beta in several mouse xenograft models of fusion-negative RMS. These findings suggest that PDGFR-beta acts as a bypass resistance pathway to IGF-1R inhibition in a subset of RMS. Therapy co-targeting these receptors may be a promising new strategy in RMS care.
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