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Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells.

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.
AuthorsYan Zhang, Qing Wang, Li Chen, Hsin-Sheng Yang
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 3 Pg. 799-809 (Mar 2015) ISSN: 1538-8514 [Electronic] United States
PMID25573956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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
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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