Identification of PDGFR-{beta} activation as a potential bypass resistance pathway in a rhabdomyosarcoma (RMS) model of acquired resistance to IGF-1 receptor blockade.

10046 Background: IGF-1R and its ligands have been shown to be potentially important therapeutic targets for sarcomas. Phase II sarcoma trials using IGF-1R blockade yielded clinically meaningful responses in unselected patients with pediatric type sarcomas. However, most responses were short-lived with rapid onset of resistance. Similarly, data from mouse xenograft RMS models showed initial response with subsequent resistance. Evaluation of tumor samples from treated mice showed persistently down-regulated IGF-1R, but rebound AKT phosphorylation, suggesting that resistance was not from loss of antibody activity against IGF-1R, but rather the result of a bypass pathway. We therefore sought to model acquired resistance in human RMS cells. Methods: Human RMS cell lines resistant to IGF-1R blockade were generated in xenografts from a highly sensitive parent cell line. Additional cell lines were selected for in vitro resistance. Parental and resistant lines were screened with a receptor phosphotyrosine array. ...