Full text release has been delayed at the author’s request until December 14, 2013.

Degree

Doctor of Philosophy, Ohio State University, Pharmacy, 2008.

Abstract

Pre-existing and acquired resistance to epidermal growth factor receptor (EGFR) inhibitors limits their clinical usefulness in patients with advanced non-small cell lung cancer (NSCLC). In this dissertation research work, the in vitro/in vivo 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, are characterized. 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 ER stress-induced, GADD153-mediated pathways. For example, ectopic expression of constitutively active Akt significantly attenuated the inhibitory effect on cell survival, and siRNA-mediated knockdown of GADD153 protected cells from undergoing apoptosis in response to drug co-treatments. Furthermore, the OSU-03012/EGFR inhibitor combination induced GADD153-mediated upregulation 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. In addition to the OSU-03012/EGFR inhibitor combinations, erlotinib in combination with HDAC inhibitor vorinostat or OSU-HDAC42 exhibits significantly enhanced anticancer activity in two EGFR-inhibitor resistant NSCLC cell lines, H1299 and H1975, by targeting signaling involved in regulation of cell survival and death at multiple levels. The erlotinib/HDAC inhibitor combination elicited massive apoptosis in both of H1299 and H1975 cell lines, suggesting that the anticancer activity of this combination strategy is independent of p53 function and EGFR mutations. Evidence indicates that this combination facilitates apoptosis through inhibition of Akt and Erk survival signaling and activation of NR4A1-mediated apoptosis. The studies presented here provide novel mechanistic rationales for the clinical use of EGFR inhibitors to possibly form more effective protocols for treating NSCLC patients.

Subject Headings

Oncology

Keywords

non-small cell lung cancer; EGFR inhibitor; HDAC inhibitor; Akt; ER stress; NR4A1

Committee / Advisors

Ching-Shih Chen, PhD (Advisor)
Roger Briesewitz, PhD (Committee Member)
F. Kay Huebner, PhD (Committee Member)
Pui-Kai Li, PhD (Committee Member)
Miguel A Villalona-Calero, MD (Committee Member)

Pages

109p.

Document number: osu1226515990
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=osu1226515990