Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors
Resource
Cancer Research 68 (8): 2820-2830
Journal
Cancer Research
Pages
2820-2830
Date Issued
2008
Date
2008
Author(s)
Wang, Yu-Chieh
Kulp, Samuel K.
Wang, Dasheng
Yang, Chih-Cheng
Sargeant, Aaron M.
Hung, Jui-Hsiang
Kashida, Yoko
Yamaguchi, Mamoru
Chen, Ching-Shih
Abstract
Preexisting and acquired resistance to epidermal growth factor receptor (EGFR) inhibitors limits their clinical usefulness in patients with advanced non-small cell lung cancer (NSCLC). This study characterizes the efficacy and mechanisms of the combination of gefitinib or erlotinib with OSU-03012, a celecoxib-derived antitumor agent, to overcome EGFR inhibitor resistance in three NSCLC cell lines, H1155, H23, and A549. The OSU-03012/EGFR inhibitor combination induced pronounced apoptosis in H1155 and H23 cells, but not in A549 cells, suggesting a correlation between drug sensitivity and basal phospho-Akt levels independently of EGFR expression status. Evidence indicates that this combination facilitates apoptosis through both Akt signaling inhibition and upregulation of endoplasmic reticulum (ER) stress-induced, GADD153-mediated pathways. For example, ectopic expression of constitutively active Akt significantly attenuated the inhibitory effect on cell survival, and small interfering RNA-mediated knockdown of GADD153 protected cells from undergoing apoptosis in response to drug cotreatments. Furthermore, the OSU-03012/EGFR inhibitor combination induced GADD153-mediated up-regulation of death receptor 5 expression and subsequent activation of the extrinsic apoptosis pathway. It is noteworthy that the ER stress response induced by this combination was atypical in that the cytoprotective pathway was not engaged. In addition, in vivo suppression of tumor growth and modulation of intratumoral biomarkers were observed in a H1155 tumor xenograft model in nude mice. These data suggest that the concomitant modulation of Akt and ER stress pathways with the OSU-03012/EGFR inhibitor combination represents a unique approach to overcoming EGFR inhibitor resistance in NSCLC and perhaps other types of cancer with elevated basal Akt activities. ?2008 American Association for Cancer Research.
SDGs
Other Subjects
celecoxib; death receptor 5; epidermal growth factor receptor kinase inhibitor; erlotinib; gefitinib; growth arrest and DNA damage inducible protein 153; osu 03012; protein kinase B; small interfering RNA; unclassified drug; animal experiment; animal model; apoptosis; article; cancer cell culture; cancer combination chemotherapy; cancer model; cell protection; cell survival; controlled study; culture medium; drug effect; drug efficacy; drug sensitivity; drug targeting; endoplasmic reticulum; enzyme activity; female; human; human cell; lung non small cell cancer; mouse; nonhuman; nude mouse; priority journal; protein expression; signal transduction; stress; tumor xenograft; upregulation; Actins; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Flow Cytometry; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazoles; Quinazolines; Receptor, Epidermal Growth Factor; Receptors, TNF-Related Apoptosis-Inducing Ligand; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides
Type
journal article
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