MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors
| Autor: | Victoria Rimkunas, Jian Tang, Alexey Lugovskoy, Rachel Rennard, Kenneth J. Olivier, Lihui Xu, Sergio Iadevaia, Birgit Schoeberl, Bryan Johnson, Jonathan Fitzgerald, Neeraj Kohli, Brian Harms, Jason Baum, Yang Jiao, Sharlene Adams, Ulrik B. Nielsen, Maja Razlog |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Receptor ErbB-3 Blotting Western Mice Nude Docetaxel Mice SCID Biology Pharmacology Antibodies Monoclonal Humanized Deoxycytidine Receptor IGF Type 1 Phosphatidylinositol 3-Kinases chemistry.chemical_compound Mice Inbred NOD Cell Line Tumor Neoplasms Antibodies Bispecific Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans ERBB3 Everolimus Receptor Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Sirolimus TOR Serine-Threonine Kinases Xenograft Model Antitumor Assays Gemcitabine Tumor Burden Oncology chemistry Cancer cell Female Taxoids Signal transduction Growth inhibition Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 13:410-425 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR–mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410–25. ©2013 AACR. |
| Databáze: | OpenAIRE |
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