A novel calcium-dependent mechanism of acquired resistance to IGF-1 receptor inhibition in prostate cancer cells

• Published in: Oncotarget 2014-10, Vol.5 (19), p.9007-9021
• Main Authors: Fahrenholtz, Cale D, Greene, Ann M, Beltran, Pedro J, Burnstein, Kerry L
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Apoptosis - drug effects; Calcium - metabolism; Calcium Chelating Agents - pharmacology; Calcium Signaling - drug effects; Calcium Signaling - genetics; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Focal Adhesion Kinase 2 - antagonists & inhibitors; Focal Adhesion Kinase 2 - metabolism; Humans; Male; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - prevention & control; Phospholipase C gamma - antagonists & inhibitors; Phospholipase C gamma - metabolism; Phosphorylation; Prostatic Neoplasms - drug therapy; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - biosynthesis; Receptor, Insulin - biosynthesis; Research Paper; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2346

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.