Journal
EXPERIMENTAL CELL RESEARCH
Volume 318, Issue 16, Pages 2014-2021Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2012.06.001
Keywords
Breast cancer; Reactive oxygen species; Tyrosine kinase inhibitors; Epidermal growth factor receptor; Tyrosine kinase
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Funding
- NIH Center [P30ES06639, P30CA22453, U54RR020843]
- Burnham Institute
- Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University
- Susan G. Komen for the Cure Career Catalyst Grant [KG081416]
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Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. (C) 2012 Published by Elsevier Inc.
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