Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bispecific / administration & dosage
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Antibodies, Bispecific / immunology
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Antibodies, Bispecific / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Deoxycytidine / administration & dosage
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Deoxycytidine / analogs & derivatives
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Docetaxel
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Everolimus
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Female
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Gemcitabine
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Humans
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, ErbB-3 / antagonists & inhibitors*
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Receptor, ErbB-3 / immunology
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Receptor, IGF Type 1 / antagonists & inhibitors*
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Receptor, IGF Type 1 / immunology
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Signal Transduction / drug effects*
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Sirolimus / administration & dosage
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Sirolimus / analogs & derivatives
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TOR Serine-Threonine Kinases / metabolism
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Taxoids / administration & dosage
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Bispecific
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Antibodies, Monoclonal, Humanized
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Taxoids
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Deoxycytidine
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Docetaxel
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Everolimus
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MTOR protein, human
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ERBB3 protein, human
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Receptor, ErbB-3
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Receptor, IGF Type 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus
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Istiratumab
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Gemcitabine