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.
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DOI：
10.18632/oncotarget.2346
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Burnstein KL
中科院分区：
文献类型：
--
作者：
Fahrenholtz CD;Greene AM;Beltran PJ;Burnstein KL
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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影响因子：
5.7
作者：
Konijeti R;Koyama S;Gray A;Barnard RJ;Said JW;Castor B;Elashoff D;Wan J;Beltran PJ;Calzone FJ;Cohen P;Galet C;Aronson WJ
通讯作者：
Aronson WJ
DOI：
10.1158/1078-0432.ccr-13-3448
发表时间：
2014-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Beltran PJ;Calzone FJ;Mitchell P;Chung YA;Cajulis E;Moody G;Belmontes B;Li CM;Vonderfecht S;Velculescu VE;Yang G;Qi J;Slamon DJ;Konecny GE
通讯作者：
Konecny GE
影响因子：
4.8
作者：
Dupont, J;Karas, M;LeRoith, D
通讯作者：
LeRoith, D
影响因子：
50.5
作者：
Cohn, A. L.;Tabernero, J.;Choo, S-P
通讯作者：
Choo, S-P
影响因子：
2.9
作者：
Mendivil, Albert;Zhou, Chunxiao;Bae-Jump, Victoria L.
通讯作者：
Bae-Jump, Victoria L.