The role of PDGFR-β activation in acquired resistance to IGF-1R blockade in preclinical models of rhabdomyosarcoma

Christine M. Heske, Choh Yeung, Arnulfo Mendoza, Joshua T. Baumgart, Leah D. Edessa, Xiaolin Wan, Lee J. Helman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)540-547
Number of pages8
JournalTranslational Oncology
Volume9
Issue number6
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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