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

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

  • Oncotarget. 2014 Oct 15;5(19):9007-21. doi: 10.18632/oncotarget.2346.
Cale D Fahrenholtz 1 Ann M Greene 1 Pedro J Beltran 2 Kerry L Burnstein 1
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 2 Oncology Research, Amgen Inc., Thousand Oaks, CA.
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.

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