title: β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.
abstract: Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/β-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and β-arrestin1-dependent ERK signaling activation. Controlled β-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further β-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: β-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of β-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zheng
authors.forename: Hongchang
authors.initials: H
authors.lastname: Shen
authors.forename: Iulian
authors.initials: I
authors.lastname: Oprea
authors.forename: Claire
authors.initials: C
authors.lastname: Worrall
authors.forename: Radu
authors.initials: R
authors.lastname: Stefanescu
authors.forename: Ada
authors.initials: A
authors.lastname: Girnita
authors.forename: Leonard
authors.initials: L
authors.lastname: Girnita
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D019390:Arrestins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D054875:Ubiquitination; D000071557:beta-Arrestins
chemical_list: D000911:Antibodies, Monoclonal; D019390:Arrestins; D016756:Immunoglobulins, Intravenous; D034741:RNA, Small Interfering; D000071557:beta-Arrestins; D017526:Receptor, IGF Type 1; C525021:figitumumab