Fitzgerald J.B.,Merrimack Pharmaceuticals One Kendal Square Suite B7201 |
Johnson B.W.,Merrimack Pharmaceuticals One Kendal Square Suite B7201 |
Baum J.,Merrimack Pharmaceuticals One Kendal Square Suite B7201 |
Adams S.,Merrimack Pharmaceuticals One Kendal Square Suite B7201 |
And 13 more authors.
Molecular Cancer Therapeutics | Year: 2014
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. Amultiplicity 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 © 2014 American Association for Cancer Research.