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: Cale D Fahrenholtz, Ann M Greene, Pedro J Beltran, Kerry L Burnstein
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 19 Pg. 9007-21 (Oct 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25344862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Calcium Chelating Agents
• ganitumab
• MTOR protein, human
• Receptor, IGF Type 1
• Receptor, Insulin
• Focal Adhesion Kinase 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Phospholipase C gamma
• Calcium

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Apoptosis (drug effects)
• Calcium (metabolism)
• Calcium Chelating Agents (pharmacology)
• Calcium Signaling (drug effects, genetics)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm
• Focal Adhesion Kinase 2 (antagonists & inhibitors, metabolism)
• Humans
• Male
• Neoplasm Recurrence, Local (drug therapy, prevention & control)
• Phospholipase C gamma (antagonists & inhibitors, metabolism)
• Phosphorylation
• Prostatic Neoplasms (drug therapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, biosynthesis)
• Receptor, Insulin (biosynthesis)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays