title: Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.
abstract: Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Kuhn
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berkova
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Richard
authors.initials: R
authors.lastname: Woessner
authors.forename: Chad C
authors.initials: CC
authors.lastname: Bjorklund
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Madden
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Sheeba K
authors.initials: SK
authors.lastname: Thomas
authors.forename: Jatin J
authors.initials: JJ
authors.lastname: Shah
authors.forename: Donna M
authors.initials: DM
authors.lastname: Weber
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D011719:Pyrazines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D007093:Imidazoles; D011719:Pyrazines; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; D017526:Receptor, IGF Type 1