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Identification of predictive biomarkers and the mechanisms of acquired resistance to epidermal growth factor receptor inhibitors : EGFR 저해제의 작용 및 내성기전 연구

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dc.contributor.advisor방영주-
dc.contributor.author김황필-
dc.date.accessioned2017-07-14T01:14:59Z-
dc.date.available2017-07-14T01:14:59Z-
dc.date.issued2014-02-
dc.identifier.other000000017921-
dc.identifier.urihttps://hdl.handle.net/10371/121765-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 협동과정 종양생물학전공, 2014. 2. 방영주.-
dc.description.abstractEpidermal growth factor receptor (EGFR) is one of the most commonly altered genes in human cancer by way of over-expression, amplification, and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation, and resistance to apoptosis. EGFR targeted therapies have been recently developed for the treatment of multiple cancer types. At the time when they were introduced in clinical practice, there was little knowledge of the molecular bases of tumor sensitivity and resistance to these novel targeted compounds.
First, epidermal growth factor receptor tyrosine kinase inhibitor has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated. I have demonstrated that lapatinib, a dual inhibitor of EGFR and HER2 TK, effectively downregulates a variety of nucleotide synthesis-related genes, including TS, and exhibits activity superior to that of gefitinib not only in HER2-amplified cells, but also in wild-type cells. As a mechanism, I have determined, for the first time, that nuclear EGFR and HER2 activate TS gene transcription, and that EGFR and HER2-bound TS promoter activities are inhibited by lapatinib treatment.
Second, although non-small cell lung cancer (NSCLC) cells with somatic mutations in EGFR initially show a dramatic response to tyrosine kinase inhibitor, these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine for threonine in 790. I showed that lapatinib revealed moderately enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Based on its dedimerization effect on EGFR and HER2, lapatinib may partially attenuate the resistance to EGFR TKI in T790M lung cancer cells.
Third, human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. The measurement of basal gene expression levels allowed us to identify Testican-1-mediated EMT as a mechanism of acquired resistance to lapatinib in HER2-gastric cancer cells. Testican-1 silencing partially restored sensitivity to lapatinib in resistant cells, implying that other signaling pathways may also be responsible for drug resistance. However, owing to the limited number of cell lines used in our experiments, it is possible that other important biological factors exist that contribute to drug resistance in HER2-positive gastric cancer.
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dc.description.tableofcontentsABSTRACT….………………………………………………...ⅰ
TABLE OF CONTENTS……….……………………………...ⅴ
LIST OF FIGURES……………………..………………..……ⅸ

. Background and Purpose…………………………………1
1. Oncogene addiction
2. Epidermal growth factor receptor as targets for cancer
therapy
3. Acquired resistance to targeted therapy
4. Purpose

Ⅱ. Lapatinib downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2………….………………………………………………...6

ABSTRACT……………..…………………………..……….....7
INTRODUCTION…………..……………………………..……9
MATERIALS AND METHODS..……………….…………..…13
RESULTS ……………………..……………………………....22
DISCUSSION ……………………………………..……….....46

Ⅲ. Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells………….……49

ABSTRACT…………..…………………………………….….50
INTRODUCTION……………………………………….……..52
MATERIALS AND METHODS..……………….……….….…56
RESULTS …………………………………..…………….…...62
DISCUSSION ………………………………………..……....88

Ⅳ. Testican-1 mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer……………..…………………….…..92

ABSTRACT……………………..……………...………….…..93
INTRODUCTION………….…………………………………..95
MATERIALS AND METHODS………………….……..…..…99
RESULTS ……..……………………..……………………....106
DISCUSSION …………………………………….………....137

Ⅴ.CONCLUSION...............................................................142

1. Lapatinib downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2
2. Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells
3. Testican-1 mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

REFERENCES…………………………………....………...145
ABSTRACT IN KOREAN……………………....………..….165
ACKNOLEDGEMENT………………………………..……..169
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dc.formatapplication/pdf-
dc.format.extent3062305 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectEGFR-
dc.subjectHER2-
dc.subjectgefitinib-
dc.subjectlapatinib-
dc.subjectcetuximab-
dc.subjectgefitinib resistance-
dc.subjectTestican-1-
dc.subjectepithelial-mesenchymal transition-
dc.subjectlapatinib resistance-
dc.subject.ddc616-
dc.titleIdentification of predictive biomarkers and the mechanisms of acquired resistance to epidermal growth factor receptor inhibitors-
dc.title.alternativeEGFR 저해제의 작용 및 내성기전 연구-
dc.typeThesis-
dc.description.degreeDoctor-
dc.citation.pagesⅹ, 170-
dc.contributor.affiliation의과대학 협동과정 종양생물학전공-
dc.date.awarded2014-02-
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