title: A novel calcium-dependent mechanism of acquired resistance to IGF-1 receptor inhibition in prostate cancer cells.
abstract: Inhibition of the mitogenic insulin-like growth factor receptor 1 (IGF-1R) signaling axis is a compelling treatment strategy for prostate cancer. Combining the IGF-1R inhibitor ganitumab (formerly AMG 479) with standard of care androgen-deprivation therapy greatly delays prostate cancer recurrence in xenograft models; however, a significant proportion of these tumors ultimately acquire resistance to ganitumab. Here we describe the development of a stable and reproducible ganitumab-resistant VCaP human prostate cancer cell derivative termed VCaP/GanR to investigate the mechanism of acquired resistance to IGF-1R inhibition. Unlike parental VCaP, VCaP/GanR did not undergo apoptosis following ganitumab treatment. VCaP/GanR did not express increased levels of IGF-1R, insulin receptor, or phospho-AKT compared to parental VCaP. VCaP/GanR exhibited increased levels of phospho-S6 indicative of increased mTOR activity. However, acquired resistance to ganitumab was not dependent on increased mTOR activity in VCaP/GanR. Phospho-proteomic arrays revealed alterations in several calcium-regulated signaling components in VCaP/GanR compared to VCaP. Reduction of intracellular calcium using cell-permeable calcium-specific chelators restored ganitumab sensitivity to VCaP/GanR through inhibition of cell-cycle progression. These data suggest a new mechanism of resistance to IGF-1R inhibition involving calcium-mediated proliferation effects. Such pathways should be considered in future clinical studies of IGF-1R inhibitors in prostate cancer.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Cale D
authors.initials: CD
authors.lastname: Fahrenholtz
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Greene
authors.affiliation: Oncology Research, Amgen Inc., Thousand Oaks, CA.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Beltran
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Burnstein
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D065096:Calcium Chelating Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000517:prevention & control; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065096:Calcium Chelating Agents; C545764:ganitumab; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051418:Focal Adhesion Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051966:Phospholipase C gamma; D002118:Calcium