mTOR-independent 4E-BP1 phosphorylation is associated with cancer resistance to mTOR kinase inhibitors

ATP -competitive mTO R kinase inhibitors (mTorKIs) are a new generation of mTO R-targeted agents with more potent anticancer activity than rapamycin in several tumor models. However, the sensitivity and resistance of cancer cells to mTorKIs remain poorly understood. In this study, we tested mTorKIs...

Full description

Saved in:
Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2012-02, Vol.11 (3), p.594-603
Main Authors: Zhang, Yanjie, Zheng, X.F. Steven
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Binding
Biology
Bioscience
Caco-2 Cells
Calcium
Cancer
Cell
Cell Line, Tumor
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - enzymology
Cycle
Drug Resistance, Neoplasm - drug effects
HCT116 Cells
HT29 Cells
Humans
Landes
Male
Mice
Mice, Nude
Organogenesis
Phosphoproteins - metabolism
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Proteins
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
Transplantation, Heterologous
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:ATP -competitive mTO R kinase inhibitors (mTorKIs) are a new generation of mTO R-targeted agents with more potent anticancer activity than rapamycin in several tumor models. However, the sensitivity and resistance of cancer cells to mTorKIs remain poorly understood. In this study, we tested mTorKIs against a large panel of colorectal cancer (CRC) cell lines, and found that mTorKIs displayed broader anti-CRC activity than rapamycin, including CRC cells with K-Ras or B-Raf mutations, suggesting that these mTorKIs are particularly useful for CRCs resistant to EGFR inhibitors. Unexpectedly, we found that 40% CRC cell lines were intrinsically drug resistant. Moreover, we discovered an mTO R-independent 4E- BP1 phosphorylation that was correlated with mTorKI resistance. Altogether, our findings provide compelling preclinical support for testing mTorKIs in human CRC clinical trials. They further reveal the existence of significant intrinsic mTorKI drug resistance in cancer cells and suggest that 4E-BP1 phosphorylation is a predictive biomarker for mTorKI sensitivity and resistance.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.11.3.19096