Oncotarget

Research Papers:

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 and Kerry L. Burnstein

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Oncotarget. 2014; 5:9007-9021. https://doi.org/10.18632/oncotarget.2346

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Abstract

Cale D Fahrenholtz1, Ann M Greene1, Pedro J Beltran2, Kerry L Burnstein1

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.

Correspondence to:

Dr. Kerry L Burnstein, e-mail: [email protected]

Key words: insulin-like growth factor receptor 1, ganitumab, AMG 479, phospho-proteomics, VCaP, castration resistance

Received: February 27, 2014     Accepted: August 11, 2014     Published: August 19, 2014

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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