進階搜尋


下載電子全文  
系統識別號 U0026-1912201221553400
論文名稱(中文) 建立一藥物篩檢平台以探討酪氨酸激酶抑制劑與新一代熱休克蛋白90抑制劑NVP-AUY922對表現突變KIT蛋白之胃腸道基質瘤的效果與機制
論文名稱(英文) Establishment of a Drug Screening Platform to Study the Effects and Mechanisms of Tyrosine kinase Inhibitors and a Novel HSPAA1 Inhibitor (NVP-AUY922) on Mutant KIT-expression GIST
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 101
學期 1
出版年 101
研究生(中文) 薛元碩
研究生(英文) Yuan-Shuo Hsueh
學號 TB8971052
學位類別 博士
語文別 英文
論文頁數 95頁
口試委員 指導教授-陳立宗
召集委員-洪文俊
口試委員-王玲美
口試委員-沈延盛
口試委員-施能耀
中文關鍵字 胃腸道基質瘤  KIT  基立克抗藥性  酪氨酸激酶抑制劑  熱休克蛋白90抑制劑  自噬作用 
英文關鍵字 gastrointestinal stromal tumors  KIT  imatinib-resistance  tyrosine kinase inhibitor  heat shock protein 90 inhibitor  autophagy 
學科別分類
中文摘要 背景
KIT基因突變為約80%胃腸道基質瘤(gastrointestinal stromal tumors)提供主要驅使致癌訊息(driven oncogenic signal)。目前基立克(Gleevec®; imatinib mesylate, IM)為治療轉移性胃腸道基質瘤的一線藥物,在80%的病人中可達到治療效果。然而,在持續的用藥過程中,胃腸道基質瘤之KIT基因可產生繼發性突變,導致IM抗藥性的發生。而第二線KIT酪氨酸激酶抑制劑舒癌特(Sutent; sunitinib malate, SU),對具IM抗藥性且繼發性突變位於KIT 外顯子17的胃腸道基質瘤之療效則相當有限。有許多針對KIT酪氨酸激酶抑制劑與熱休克蛋白90抑制劑,用於對IM或SU有抗藥性之病人的研究在進行中,然而目前尚無突破性發展。在本研究中,我們使用市面上可取得之酪氨酸激酶抑制劑與新一類熱休克蛋白90抑制劑AUY922,探討其用於治療對IM或SU有抗藥性之胃腸道基質瘤病人的可行性,以及相關的作用機轉。
方法與結果
首先,我們在COS-1 細胞株中建立了在病人中常見的原發性+/-繼發性之KIT 突變基因的抗藥性篩檢平台,並以市面上可取得的酪氨酸激酶抑制劑,依其臨床上的血中穩定濃度,來比較這些藥物對突變株 KIT蛋白質磷酸化的抑制效果。另外,針對藥物對外顯子11/17突變KIT的結果,我們使用GIST48細胞株的生長抑制效果來做進一步確認,同時利用分子模型來探討抗藥性之機轉。數據顯示,相較於繼發性突變於外顯子17的KIT 蛋白,SU可有效抑制繼發性突變位於外顯子13或14的KIT 蛋白質磷酸化程度,此結果與臨床上的發現一致。另外,相較於其他酪氨酸激酶抑制劑,nilotinib和sorafenib可有效抑制繼發性突變位於外顯子17的KIT 蛋白質磷酸化程度與GIST48細胞的生長。分子模型的研究則發現,同時具有外顯子11大片段缺失與外顯子17點突變的KIT蛋白,結構上會從原本的不活化態趨向完全活化態,並與nilotinib和sorafenib形成較穩定的結合。
另一方面,我們證明AUY922會造成對IM敏感的GIST882細胞與對IM具抗藥性的GIST48細胞中,突變 KIT蛋白質表現總量與磷酸化程度的減少,並引發細胞凋亡,進而抑制細胞生長。利用cyclohexamide處理抑制細胞內蛋白質之合成後,加入AUY922會加速GIST細胞內KIT蛋白質降解。若利用藥物抑制proteasome或是自噬作用等蛋白質降解路徑,均可減少AUY922造成KIT降解的程度。除此之外,抑制自噬作用會造成未經AUY922處理GIST細胞KIT蛋白質表現量的增加,也證實自噬作用參與內生性KIT蛋白質的循環。自噬作用在KIT內生性循環與AUY922所引起降解過程中的角色,也進一步經由KIT蛋白質與MAP1LC3B、acridine orange、SQSTM1所標記的autophagosome共位現象,與干擾autophagsome形成之必要蛋白質BECN1或ATG5生成等實驗中獲得證實。此外,實驗結果也指出,AUY922亦會導致KIT mRNA表現量的減少,然其機轉並非影響KIT mRNA的降解,而是透過降低轉錄作用造成。數據顯示,在AUY922處理後,GIST細胞中多種轉錄因子,如CEBP、TP53、RELA與HIF1A的活性及細胞核中的表現量均會降低。 利用DNA結合力沉澱法與染色質免疫沉澱法,我們進一步證實TP53可結合至KIT promoter上-365到-30的區域,並且在AUY922處理後,造成結合至KIT promoter上的TP53減少。
結論
總結來說,我們發現對IM具有抗藥性且繼發性突變位於外顯子17的胃腸道基質瘤,nilotinib和sorafenib比SU有更佳的抑制效果。另外,AUY922的結果不止強調其用於治療有KIT表現之胃腸道基質瘤的可行性,同時也率先證實在胃腸道基質瘤細胞株GIST882與GIST48中,自噬作用參與內生性與熱休克蛋白90抑制劑所造成的KIT蛋白降解。
英文摘要 Background
Advanced gastrointestinal stromal tumors (GIST), a KIT oncogene-driven tumor, on imatinib mesylate (IM) treatment may develop secondary KIT mutations to confer IM-resistant phenotype. Second-line sunitinib malate (SU) therapy is largely ineffective for IM-resistant GISTs with secondary exon 17 (activation-loop domain) mutations. Nowadays, several KIT tyrosine kinase inhibitors (TKIs) and heat shock protein 90 (HSP90AA1) inhibitors are under investigation for IM and/or SU-resistant GIST patients. However, there is no notable improvement. In this study, we used commercial available TKIs and a new class of HSP90AA1 inhibitor, NVP-AUY922 (AUY922), to evaluate their potencies for treatment on IM and/or SU-resistant GISTs and to clarify the detailed mechanisms.
Methods and Results
First, we established an in vitro cell-based platform consisting of a series of COS-1 cells expressing KIT cDNA constructs encoding common primary±secondary mutations observed in GISTs, to compare the activity of several commercially available TKIs on inhibiting the phosphorylation of mutant KIT proteins at their clinically achievable plasma steady-state concentration (Css). The inhibitory efficacies on KIT exon 11/17 mutants were further validated by growth inhibition assay on GIST48 cells, and underlying molecular-structure mechanisms were investigated by molecular modeling. Our results showed that SU more effectively inhibited mutant KIT with secondary exon 13 or 14 mutations than those with secondary exon 17 mutations, as clinically indicated. On contrary, at individual Css, nilotinib and sorafenib more profoundly inhibited the phosphorylation of KIT with secondary exon 17 mutations and the growth of GIST48 cells than IM, SU, and dasatinib. Molecular modeling analysis showed fragment deletion of exon 11 and point mutation on exon 17 would lead to a shift of KIT conformational equilibrium toward active form, for which nilotinib and sorafenib bound more stably than IM and SU.
In the other hand, we demonstrated that AUY922 is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the IM-sensitive GIST882 and IM-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phospho-KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange-, or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. In addition, AUY922 could reduce KIT mRNA at transcription level without affecting its mRNA stability. Further studies showed that AUY922 treatment would reduce the nuclear activities and protein levels of several transcription factors, such as CEBP, TP53, RELA, and HIF1A in GIST cells. Experiments using DNA affinity precipitation and chromatin immune-precipitation assays showed that TP53 could bind on KIT promoter region (from -365 to -30 nucleotides upstream of the transcriptional start site), and its binding activity was significantly reduced after AUY922 treatment.
Conclusions
Taken together, we show that nilotinib and sorafenib are more active in IM-resistant GISTs with secondary exon 17 mutation than SU that deserve further clinical investigation. Moreover, the results of AUY922 not only highlight its potential application for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation in GIST882 and GIST48 cells.
論文目次 中文摘要 1
Abstract 3
Acknowledgement 6
Contents 8
Table of contents 10
Figure of contents 11
Appendixes of contents 12
Abbreviation 13
Introduction 14
Gastrointestinal stromal tumor 14
Immunohistochemical markers in the diagnosis of GIST 16
Current therapies for GIST 19
Resistance mechanisms to IM 20
Second-line treatment: Sutent 22
Developing therapy for IN/SU-resistant GISTs 22
Aims and overview of Thesis 25
Material and methods 27
Cell lines and reagents 27
Construction of the KIT mutants 28
Transient transfection 28
Drug treatment 29
Immunoblotting studies 30
Growth inhibition assay 31
Clonogenic assay 31
Milliplex analysis 31
Molecular modeling and docking 32
RNA interference 33
Fluorescent immunostaining and acridine orange staining 33
Flow cytometry 34
RNA extraction and quantitative analysis of KIT mRNA 34
Protein fractionation 35
Transcription factor array 35
DNA affinity binding assay 36
Chromatin immunoprecipitation (ChIP) assay 37
Results 39
Integration efforts for TKIs potencies to imatinib-resistant KIT mutants : KIT as a model 39
Effects of TKIs on KIT with single mutation expressed in COS-1 cells 39
Effects of TKIs on KIT mutants with secondary ATP-binding domain mutations 40
Effects of TKIs on KIT mutants with secondary activation-loop domain mutations
41
Virtual molecular modeling/docking analysis 41
Screening new compounds targeted to mutant KIT proteins 43
Inhibition of heat-shock protein 90 induced GIST cells death and downregulated KIT transcriptional and posttranslation level 43
AUY922 downregulated phospho- and total KIT expression 43
The cytotoxic effect of AUY922 in GIST48 and GIST882 cells 45
The enhancement of KIT protein degradation by AUY922 46
AUY922-induced autophagy led to KIT reduction 46
Autophagy was also involved in endogenous KIT turnover in GIST cells 47
AUY922 reduced KIT mRNA expression level and downregulated the TP53 transcriptional activity, nuclear partition, and its binding to KIT promoter 48
Discussion 50
Integration efforts for TKIs potencies to imatinib-resistant KIT mutants : KIT as a model 50
Inhibition of heat-shock protein 90 induced GIST cells death and downregulated KIT transcriptional and posttranslation level 52
Conclusions 57
References 58
Tables 69
Figures 72
Appendixes 92
參考文獻 Abraham SC, Krasinskas AM, Hofstetter WL, et al. "Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. Am J Surg Pathol. 31:1629-35, 2007
Antonescu CR, Sommer G, Sarran L, et al. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res. 9:3329-37, 2003
Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 11:4182-90, 2005
Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. 23:4152-61, 2005
Banerji U. Heat shock protein 90 as a drug target: some like it hot. Clin Cancer Res. 15:9-14, 2009
Bauer S, Yu LK, Demetri GD, et al. Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res. 66:9153-61, 2006
Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 92:657-62, 2001
Bjørkøy G, Lamark T, Brech A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 171:603-14, 2005
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 26:620-5, 2008a
Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 26:626-32, 2008b
Blay P, Astudillo A, Buesa JM, et al. Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin Cancer Res. 10:4089-95, 2004
Blume-Jensen P, Claesson-Welsh L, Siegbahn A, et al. Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J. 10:4121-8, 1991
Brough PA, Aherne W, Barril X, et al. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 51:196-218, 2008
Burger H, van Tol H, Boersma AW, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 104:2940-2, 2004
Casteran N, De Sepulveda P, Beslu N, et al. Signal transduction by several KIT juxtamembrane domain mutations. Oncogene. 22:4710-22, 2003
Cauchi C, Somaiah N, Engstrom PF, et al. Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib. Cancer Chemother Pharmacol. 69: 977-82, 2012
Chen H, Ko JM, Wong VC, et al. LTBP-2 confers pleiotropic suppression and promotes dormancy in a growth factor permissive microenvironment in nasopharyngeal carcinoma. Cancer Lett. 325:89-98, 2012
Cieslik K, Zhu Y, Wu KK. Salicylate suppresses macrophage nitric-oxide synthase-2 and cyclo-oxygenase-2 expression by inhibiting CCAAT/enhancer-binding protein-beta binding via a common signaling pathway. J Biol Chem. 277:49304-10, 2002
Corless CL, McGreevey L, Haley A, et al. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol. 160:1567-72, 2002
Corless CL, Heinrich MC, Duensing A, et al. Proc AACR. 44:abstr.R4447, 2003
Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 22:3813-25, 2004
Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 23:5357-64, 2005
Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 3:557-86, 2008
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 11:865-78, 2011
Date RS, Stylianides NA, Pursnani KG, et al. Management of gastrointestinal stromal tumours in the Imatinib era: a surgeon's perspective. World J Surg Oncol. 6:77, 2008
Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 128:270-9, 2005
Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 42:1093-103, 2006
DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 231:51-8, 2000
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 368:1329-38, 2006
Demetri GD, Casali PG, Blay JY, et al. A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res. 15:5910-6, 2009a
Demetri GD, Lo Russo P, MacPherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res. 15:6232-40, 2009b
Demetri GD, Le Cesne A, von Mehren M, et al. Final results from a phase III study of IPI-504 (retaspimycin hydrochloride) versus placebo in patients (pts) with gastrointestinal stromal tumors (GIST) following failure of kinase inhibitor therapies. ASCO Gastrointestinal Cancers Symposium. abstr.64, 2010a
Demetri GD, Mehren MV, Antonescu CR, et al. NCCN task force report: Update on the management of patients with gastrointestinal stromal tumors, JNCCN Journal of the National Comprehensive Cancer Network, 8: 2010b
Demetri GD, Heinrich MC, Chmielowski B, et al. An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST. J Clin Oncol. 29:abstr.10001, 2011.
Duensing A, Joseph NE, Medeiros F, et al. Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res. 64:5127-31, 2004a
Duensing A, Medeiros F, McConarty B, et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene. 23:3999-4006, 2004b
Egorin MJ, Rosen DM, Wolff JH, et al. Metabolism of 17-(allylamino)-17- demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res. 58:2385-96, 1998
Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 32:210-8, 2008
Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 24:25-35, 2006
Finlay GJ, Baguley BC, Wilson WR. A semiautomated microculture method for investigating growth inhibitory effects of cytotoxic compounds on exponentially growing carcinoma cells. Anal Biochem. 139:272-7, 1984
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 33:459-65, 2002
Fletcher JA, Corless CL, Dimitrijevic S, et al. Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST) Proc Am Soc Clin Oncol. 22, 2003
Floris G, Debiec-Rychter M, Wozniak A, et al. The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. Mol Cancer Ther. 10:1897-908, 2011a
Floris G, Sciot R, Wozniak A, et al. The Novel HSP90 inhibitor, IPI-493, is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations. Clin Cancer Res. 17:5604-14, 2011b
Fumo G, Akin C, Metcalfe DD, et al. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood. 103:1078-84, 2004
Gajiwala KS, Wu JC, Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 106:1542-7, 2009
Gambacorti-Passerini C, Zucchetti M, Russo D, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res. 9:625-32, 2003
Gästeiger J, Marsili M. Iterative partial equalization of orbital electronegativity - A rapid access to atomic charges. Tetrahedron. 36:3219-28, 1980
George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial.. J Clin Oncol. 30:2401-7, 2012
Goettsch WG, Bos SD, Breekveldt-Postma N, et al. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer 41:2868-72, 2005
Goetz MP, Toft D, Reid J, et al. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol. 23:1078-87, 2005
Gounder MM, Maki RG. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor. Cancer Chemother Pharmacol. 67 Suppl 1:S25-43, 2011
Guo T, Agaram NP, Wong GC, et al. Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res. 13:4874-81, 2007
Guo T, Hajdu M, Agaram NP, et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res. 15:6862-70, 2009
Heath EI, Gaskins M, Pitot HC, et al. A phase II trial of 17-allylamino-17- demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Prostate Cancer. 4:138-41, 2005
Heinrich MC, Blanke CD, Druker BJ, et al. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 20:1692-703, 2002a
Heinrich MC, Rubin BP, Longley BJ, et al. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 33:484-95, 2002b
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 21:4342-9, 2003a
Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 299:708-10, 2003b
Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 24:4764-74, 2006
Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 26:5352-9, 2008
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 279:577-80, 1998
Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 125:660-7, 2003
Huizinga JD, Thuneberg L, Kluppel M, et al. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 373:347-9, 1995
Huynh H, Lee JW, Chow PK, et al. Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol Cancer Ther. 8:152-9, 2009
Ide S, Motwani M, Jensen MR, et al. Pharmacodynamics and pharmacokinetics of AUY922 in a phase I study of solid tumor patients. J Clin Oncol. 29:abstr.3533, 2009
Isakson P, Bjørås M, Bøe SO, et al. Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. Blood. 116:2324-31, 2010
Isozaki K, Terris B, Belghiti J, et al. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol. 157:1581-5, 2000
Italiano A, Cioffi A, Coco P, et al. Patterns of Care, Prognosis, and Survival in Patients with Metastatic Gastrointestinal Stromal Tumors (GIST) Refractory to First-Line Imatinib and Second-Line Sunitinib. Ann Surg Oncol. 19:1551-9, 2012
Janeway KA, Liegl B, Harlow A, et al. Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res. 67:9084-8, 2007
Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 39:1411-9, 2008
Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 425:407-10, 2003
Kang HJ, Nam SW, Kim H, et al. Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene. 24:1066-74, 2005
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 354:2542-51, 2006
Kelland LR, Sharp SY, Rogers PM, et al. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst. 91:1940-9, 1999
Kim KP, Ryu MH, Yoo C, et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol. 68:285-91, 2011
Kindblom LG, Remotti HE, Aldenborg F, et al. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 152:1259-69, 1998
Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial. J Clin Oncol 29:abstr.10009, 2011
Kondo Y, Kanzawa T, Sawaya R, et al. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726-34, 2005
Kontogianni-Katsarou K, Dimitriadis E, Lariou C, et al. KIT exon 11 codon 557/558 deletion/insertion mutations define a subset of gastrointestinal stromal tumors with malignant potential. World J Gastroenterol. 14:1891-7, 2008
Kraft C, Peter M, Hofmann K. Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol. 12:836-41, 2010
Lamark T, Johansen T. Autophagy: links with the proteasome. Curr Opin Cell Biol. 22:192-8, 2010
Lasota J, Dansonka-Mieszkowska A, Stachura T, et al. Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol. 16:1257-64, 2003
Lasota J, Dansonka-Mieszkowska A, Sobin LH, et al. A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest. 84:874-83, 2004
Lasota J, Stachura J, Miettinen M. GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Lab Invest. 86:94-100, 2006
Lasota J, Corless CL, Heinrich MC, et al. Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Mod Pathol. 21:476-84, 2008a
Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 53:245-66, 2008b
Lee HE, Kim MA, Lee HS, et al. Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining. J Clin Pathol. 61:722-9, 2008
Lev S, Blechman J, Nishikawa S, et al. Interspecies molecular chimeras of kit help define the binding site of the stem cell factor. Mol Cell Biol. 13:2224-34, 1993
Li CF, Huang WW, Wu JM, et al. Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res. 14:7822-31, 2008
Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch. 456:111-27, 2010
Lim KH, Huang MJ, Chen LT, et al. Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors. Med Oncol. 25:207-13, 2008
Lin TY, Bear M, Du Z, et al. The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp Hematol. 36:1266-77, 2008
Maeda H, Yamagata A, Nishikawa S, et al. Requirement of c-kit for development of intestinal pacemaker system. Development. 116:369-75, 1992
Mahadevan D, Cooke L, Riley C, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 26:3909-19, 2007
Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 101:2368-73, 2003
Marcu MG, Schulte TW, Neckers L. Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. J Natl Cancer Inst. 92:242-8, 2000
Martin J, Poveda A, Llombart-Bosch A, et al. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol. 23:6190-8, 2005
Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol. 29:1373-81, 2005a
Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 29:52-68, 2005b
Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 23:70-83, 2006a
Miettinen M, Makhlouf H, Sobin LH, et al. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 30:477-89, 2006b
Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol. 33:1401-8, 2009
Mimnaugh EG, Xu W, Vos M, et al. Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther. 3:551-66, 2004
Mol CD, Lim KB, Sridhar V, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem. 278:31461-4, 2003
Mol CD, Dougan DR, Schneider TR, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem. 279:31655-63, 2004
Montemurro M, Schoffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumors resistant to both imatinib and sunitinib. Eur J Cancer. 45:2293-7, 2009
Motegi A, Sakurai S, Nakayama H, et al. PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors. Pathol Int. 55:106-12, 2005
Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 103:821-9, 2005
Olzmann JA, Chin LS. Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway. Autophagy. 4:85-7, 2008
O'Riain C, Corless CL, Heinrich MC, et al. Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features. Am J Surg Pathol. 29:1680-3, 2005
Ou WB, Zhu MJ, Demetri GD, et al. Protein kinase C-theta regulates KIT expression and proliferation in gastrointestinal stromal tumors. Oncogene. 27:5624-34, 2008
Pandey UB, Nie Z, Batlevi Y, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 447:859-63, 2007
Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 282:24131-45, 2007
Park SH, Ryu MH, Ryoo BY, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012. [Epub ahead of print]
Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 135:1298-310, 2011
Pauls K, Merkelbach-Bruse S, Thal D, et al. PDGFRalpha- and c-kit-mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features. Histopathology. 46:166-75, 2005
Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 22:935-42, 2004
Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol. 27:179-87, 2005
Purcell WP, Singer JA. A brief review and table of semiempirical parameters used in Hückel molecular orbital method. J Chem Eng Data. 12:235-246, 1967
Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 533:327-40, 2006
Robinson TL, Sircar K, Hewlett BR, et al. Gastrointestinal stromal tumors may originate from a subset of CD34-positive interstitial cells of Cajal. Am J Pathol. 156:1157-63, 2000
Ronnen EA, Kondagunta GV, Ishill N, et al. A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma. Invest New Drugs. 24:543-6, 2006
Rossi G, Valli R, Bertolini F, et al. PDGFR expression in differential diagnosis between KIT-negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract. Histopathology. 46:522-31, 2005
Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 61:8118-21, 2001
Sambol EB, Ambrosini G, Geha RC, et al. Flavopiridol targets KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells. Cancer Res. 66:5858-66, 2006
Sawaki A, Nishida T, Doi T, et al. Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer. 117:4633–41, 2011
Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 66:473-81, 2006
Shaid S, Brandts CH, Serve H, et al. Ubiquitination and selective autophagy. Cell Death Differ. doi: 10.1038/cdd.2012.72., 2012
Sharma SV, Agatsuma T, Nakano H. Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol. Oncogene. 16:2639-45, 1998
Shen S, Zhang P, Lovchik MA, et al. Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy. J Cell Biol. 185:629-39, 2009
Shin Y, Klucken J, Patterson C, et al. The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem. 280:23727-34, 2005
Sleijfer S, Wiemer E, Seynaeve C, et al. Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. Oncologist. 12:719-26, 2007
Solit DB, Osman I, Polsky D, et al. Phase II trial of 17-allylamino-17- demethoxygeldanamycin in patients with metastatic melanoma. Clin Cancer Res. 14:8302-7, 2008
Strumberg D, Clark JW, Awada A, et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. 12:426-37, 2007
Tamborini E, Pricl S, Negri T, et al. Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients. Oncogene. 25:6140-6, 2006
Theou N, Gil S, Devocelle A, et al. Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. Clin Cancer Res. 11:7593-8, 2005
Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol 29:abstr.10006, 2011
Tryggvason G, Gislason HG, Magnusson MK, et al. Gastrointestinal stromal tumors in Iceland, 1990-2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 117:289-93, 2005
Vaishampayan UN, Burger AM, Sausville EA, et al. Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin. Clin Cancer Res. 16:3795-804, 2010
van der Zwan SM, DeMatteo RP. Gastrointestinal stromal tumor: 5 years later. Cancer. 104:1781-8, 2005
Vetto JT. Role of imatinib in the management of early, operable, and advanced GI stromal tumors (GISTs). Onco Targets Ther. 2:151-9, 2009
Vilenchik M, Solit D, Basso A, et al. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol. 11:787-97, 2004
Wang Z, Cao L, Kang R, et al. Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein. Autophagy. 7:401-11, 2011
Warrens AN, Jones MD, Lechler RI. Splicing by overlap extension by PCR using asymmetric amplification: an improved technique for the generation of hybrid proteins of immunological interest. Gene. 186:29-35, 1997
Weidberg H, Shvets E, Elazar Z. Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem. 80:125-56, 2011
Weinstein IB, Joe A. Oncogene addiction. Cancer Res 68:3077-80; discussion 3080, 2008
West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 165:107-13, 2004
Whitesell L, Cook P. Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells. Mol Endocrinol. 10:705-12, 1996
Willis MS, Townley-Tilson WH, Kang EY, et al. Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res. 106:463-78, 2010
Woodall CE, 3rd, Brock GN, Fan J, et al. An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system. Arch Surg. 144:670-8, 2009
Zheng S, Chen LR, Wang HJ, et al. Analysis of mutation and expression of c-kit and PDGFR-alpha gene in gastrointestinal stromal tumor. Hepatogastroenterology. 54:2285-90, 2007
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2017-12-24起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2014-12-24起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw