Date of Graduation

12-2013

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Zhen Fan

Committee Member

Peng Huang

Committee Member

Jonathan M. Kurie

Committee Member

Chun Li

Committee Member

David J. McConkey

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in the majority of head and neck cancers. The anti-EGFR antibody cetuximab has been approved by the FDA for the treatment of head and neck cancers, however, only a small fraction of patients respond to cetuximab treatment. Further investigation to understand the mechanisms underlying cetuximab-mediated EGFR-targeted therapy and to develop novel therapeutic strategies to improve the efficacy of cetuximab is urgently needed. In the present study, we elucidated the mechanism of cetuximab in radiosensitization, and discovered novel functions of cetuximab in glycolysis inhibition and cellular redox status regulation. We found that cetuximab inhibits radiation-induced hypoxia inducible factor 1 (HIF-1), which is required for the radiosensitization role of cetuximab. We also found that cetuximab inhibits glycolysis in cancer cells through downregulation of HIF-1, which explains the cytostatic effect of cetuximab in the perspective of cancer metabolism. In addition, we discovered a novel function of cetuximab in decreasing the anti-oxidant capacity of cancer cells through downregulating glutamine transporter ASCT2, which is in an EGFR-kinase activity inhibition independent manner. Applications of these mechanism studies lead to findings of novel therapeutic targets to improve cetuximab responses and/or overcome cetuximab resistance. We proved that targeting HIF-1 improves response of cetuximab-resistant cancer cells to the combination treatment of cetuximab and radiation, while targeting lactate dehydrogenase A (LDH-A) restores the role of cetuximab in cell cycle arrest in cetuximab-resistant cancer cells. Moreover, targeting pyruvate dehydrogenase kinase 1 (PDK1), in combination with cetuximab, leads to a synergetic and synthetic lethality in cancer cells, which bypasses most currently known cetuximab resistant mechanisms. In summary, our findings provide novel mechanistic insights into cetuximab-mediated EGFR targeted therapy and suggest novel therapeutic strategies for enhancing the response of cancer patients to cetuximab treatment.

Keywords

EGFR, Cetuximab, Radiation, HIF-1, Warburg effect, Cancer metabolism, Redox homeostasis, ASCT2

Available for download on Wednesday, August 22, 2018

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