Abstract |
Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906-resistant and -sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906-resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer.
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Authors | Yan Zhang, Qing Wang, Li Chen, Hsin-Sheng Yang |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 14
Issue 3
Pg. 799-809
(Mar 2015)
ISSN: 1538-8514 [Electronic] United States |
PMID | 25573956
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | ©2015 American Association for Cancer Research. |
Chemical References |
- 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
- Apoptosis Regulatory Proteins
- Imidazoles
- PDCD4 protein, human
- PF-4708671
- Piperazines
- Protein Kinase Inhibitors
- Pyrazines
- RNA-Binding Proteins
- Receptor, IGF Type 1
- Ribosomal Protein S6 Kinases, 70-kDa
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Topics |
- Animals
- Apoptosis Regulatory Proteins
(metabolism)
- Caco-2 Cells
- Carcinoma
(drug therapy, metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Colorectal Neoplasms
(drug therapy, metabolism)
- Drug Resistance, Neoplasm
(drug effects)
- Female
- HCT116 Cells
- HT29 Cells
- Humans
- Imidazoles
(pharmacology)
- Mice
- Mice, Nude
- Piperazines
(pharmacology)
- Protein Kinase Inhibitors
(pharmacology)
- Pyrazines
(pharmacology)
- RNA-Binding Proteins
(metabolism)
- Receptor, IGF Type 1
(antagonists & inhibitors)
- Ribosomal Protein S6 Kinases, 70-kDa
(antagonists & inhibitors)
- Xenograft Model Antitumor Assays
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