The Role of PDGFR-β Activation in Acquired Resistance to IGF-1R Blockade in Preclinical Models of Rhabdomyosarcoma.
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 β (PDGFR-β) 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-β 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-β inhibition in vitro. In vivo studies have confirmed the enhanced effect of targeting IGF-1R and PDGFR-β in several mouse xenograft models of fusion-negative RMS. These findings suggest that PDGFR-β 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.
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: christine.heske@nih.gov.
Christine M
CM
Heske
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Choh
C
Yeung
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Arnulfo
A
Mendoza
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Joshua T
JT
Baumgart
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Leah D
LD
Edessa
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Xiaolin
X
Wan
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Lee J
LJ
Helman