title: Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia.
abstract: The receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) is implicated in various tumor entities including chronic lymphocytic leukemia (CLL), but its functional significance in this disease remains poorly characterized. Here, we show that the IGF1R protein is overexpressed in various CLL subsets, suggesting a contribution to CLL pathology. Indeed, we show that IGF1R knockdown in primary human CLL cells compromised their viability. Likewise, IGF1R inhibition with 3 structurally distinct compounds induced apoptosis, even in the presence of protective stroma components. Furthermore, IGF1R inhibition effectively limited CLL development in Eμ-TCL1 transgenic mice and of primary human CLL xenografts. In agreement with its prosurvival function, IGF1R inhibition affected the phosphorylation and/or expression of multiple signaling proteins. The multikinase inhibitor sorafenib yielded similar effects on these signaling elements as IGF1R inhibitors. Indeed, IGF1R appears to be a direct sorafenib target because sorafenib decreased IGF1R expression and phosphorylation, counteracted insulin-like growth factor-1 (IGF-1) binding to CLL cells, and lowered the in vitro kinase activity of recombinant, purified IGF1R. Thus, we demonstrate that blockade of IGF1R-mediated signaling represents a novel mechanism of action for sorafenib in CLL. Importantly, IGF1R inhibitors compromise CLL viability in their microenvironment context, implicating this RTK as a promising therapeutic target.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Niuscha
authors.initials: N
authors.lastname: Yaktapour
authors.forename: Rudolf
authors.initials: R
authors.lastname: Übelhart
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.forename: Konrad
authors.initials: K
authors.lastname: Aumann
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1