title: Generation of a conditionally transformed murine embryonic fibroblast cell line using doxycycline-dependent IGF-1R overexpression.
abstract: The insulin-like growth factor I receptor (IGF1-R) system has long been implicated in cancer and is a promising target for tumor therapy. Besides in vitro screening assays, the discovery of specific inhibitors against IGF-1R requires relevant cellular models, ideally applicable to both in vitro and in vivo studies. With this aim in mind, the authors generated an inducible cell line using the tetracycline-responsive gene expression system to mimic the effects of therapeutic inhibition of the IGF-1R both in vitro and on established tumors in vivo. Inducible overexpression of IGF-1R in murine embryonic fibroblasts was achieved and resulted in the transformation of the cells as verified by their ability to grow in soft agar and in nude mice. Continuous repression of exogenous IGF-1R expression completely prevented outgrowth of the tumors. Furthermore, induced repression of IGF-1R expression in established tumors resulted in regression of the tumors. Interestingly, however, IGF-1R-independent relapse of tumor growth was observed upon prolonged IGF-1R repression. The IGF-1R cell line generated using this approach was successfully employed to test reference small-molecule inhibitors in vitro and an IGF-1R-specific inhibitory antibody, EM164, in vivo. Besides efficacy as a read-out, phospho-AKT could be identified as a pharmacodynamic biomarker, establishing this cell line as a valuable tool for the preclinical development of IGF-1R inhibitors.
authors: ProQinase GmbH, Tumor Biology Center, Freiburg, Germany. r.graeser17@gmail.com
authors: Ralph
authors: R
authors: Graeser
authors: Patricia
authors: P
authors: Vrignaud
authors: Norbert
authors: N
authors: Esser
authors: Sarah
authors: S
authors: Umber
authors: Ute
authors: U
authors: Zirrgiebel
authors: Marielle
authors: M
authors: Chiron
authors: Christoph
authors: C
authors: Schaechtele
authors: Michael H G
authors: MH
authors: Kubbutat
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004318:Doxycycline / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005347:Fibroblasts; D051379:Mice; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D017526:Receptor, IGF Type 1; D004318:Doxycycline