A novel calcium-dependent mechanism of acquired resistance to IGF-1 receptor inhibition in prostate cancer cells
Year: 2014
Type: article
Abstract: // Cale D Fahrenholtz 1 , Ann M Greene 1 , Pedro J Beltran 2 , Kerry L Burnstein 1 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.
Source: Oncotarget
Institutions: University of Miami, Amgen (United States)
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W1933713383