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

Cale D. Fahrenholtz, Ann M. Greene, Pedro J. Beltran, Kerry L. Burnstein

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9007-9021
Number of pages15
JournalOncotarget
Volume5
Issue number19
DOIs
StatePublished - Jan 1 2014

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Keywords

  • AMG 479
  • Castration resistance
  • Ganitumab
  • Insulin-like growth factor receptor 1
  • Phospho-proteomics
  • VCaP

ASJC Scopus subject areas

  • Oncology

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