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β-Arrestin-biased a...
β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma
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- Zheng, HY (författare)
- Karolinska Institutet
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Shen, HC (författare)
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- Oprea, I (författare)
- Karolinska Institutet
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- Worrall, C (författare)
- Karolinska Institutet
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Stefanescu, R (författare)
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- Girnita, A (författare)
- Karolinska Institutet
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- Girnita, L (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2012-11-27
- 2012
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 109:50, s. 20620-20625
- Relaterad länk:
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https://www.pnas.org...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- 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.
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