請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20423
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 俞松良 | |
dc.contributor.author | Chih-An Lin | en |
dc.contributor.author | 林志安 | zh_TW |
dc.date.accessioned | 2021-06-08T02:48:13Z | - |
dc.date.copyright | 2017-09-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-18 | |
dc.identifier.citation | 1. Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. Journal of thoracic disease. 2013;5 Suppl 5:S463-78.
2. Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. Journal of clinical oncology. 2013;31:1070-80. 3. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer research. 2013;19:2240-7. 4. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011;3:75ra26. 5. Ahn S, Hwang SH, Han J, Choi YL, Lee SH, Ahn JS, et al. Transformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases. Journal of pathology and translational medicine. 2016;50:258-63. 6. Doyle LA, Borges M, Hussain A, Elias A, Tomiyasu T. An adherent subline of a unique small-cell lung cancer cell line downregulates antigens of the neural cell adhesion molecule. The Journal of clinical investigation. 1990;86:1848-54. 7. Sutherland KD, Proost N, Brouns I, Adriaensen D, Song JY, Berns A. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer cell. 2011;19:754-64. 8. Calbo J, van Montfort E, Proost N, van Drunen E, Beverloo HB, Meuwissen R, et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer cell. 2011;19:244-56. 9. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA: a cancer journal for clinicians. 2017;67:7-30. 10. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nature reviews Cancer. 2014;14:535-46. 11. Langer CJ, Besse B, Gualberto A, Brambilla E, Soria JC. The evolving role of histology in the management of advanced non-small-cell lung cancer. Journal of clinical oncology. 2010;28:5311-20. 12. Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, et al. Clonal genetic alterations in the lungs of current and former smokers. Journal of the National Cancer Institute. 1997;89:857-62. 13. Wistuba, II, Berry J, Behrens C, Maitra A, Shivapurkar N, Milchgrub S, et al. Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2000;6:2604-10. 14. Pretreatment evaluation of non-small-cell lung cancer. The American Thoracic Society and The European Respiratory Society. American journal of respiratory and critical care medicine. 1997;156:320-32. 15. Beadsmoore CJ, Screaton NJ. Classification, staging and prognosis of lung cancer. European journal of radiology. 2003;45:8-17. 16. Woodring JH, Stelling CB. Adenocarcinoma of the lung: a tumor with a changing pleomorphic character. American journal of roentgenology. 1983;140:657-64. 17. Kazerooni EA, Bhalla M, Shepard JA, McLoud TC. Adenosquamous carcinoma of the lung: radiologic appearance. American journal of roentgenology. 1994;163:301-6. 18. Chaudhuri MR. Primary pulmonary cavitating carcinomas. Thorax. 1973;28:354-66. 19. Herbst RS, Heymach JV, Lippman SM. Lung cancer. The New England journal of medicine. 2008;359:1367-80. 20. Shin MS, Jackson LK, Shelton RW, Jr., Greene RE. Giant cell carcinoma of the lung. Clinical and roentgenographic manifestations. Chest. 1986;89:366-9. 21. Pearlberg JL, Sandler MA, Lewis JW, Jr., Beute GH, Alpern MB. Small-cell bronchogenic carcinoma: CT evaluation. AJR American journal of roentgenology. 1988;150:265-8. 22. Hirsch FR, Matthews MJ, Aisner S, Campobasso O, Elema JD, Gazdar AF, et al. Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer. 1988;62:973-7. 23. Blakely CM, Bivona TG. Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance. Cancer discovery. 2012;2:872-5. 24. Xue C, Wyckoff J, Liang F, Sidani M, Violini S, Tsai KL, et al. Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer research. 2006;66:192-7. 25. Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. Journal of clinical oncology. 2002;20:3815-25. 26. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. Journal of clinical oncology. 2003;21:2787-99. 27. Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. Journal of clinical oncology. 2012;30:433-40. 28. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-37. 29. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al. Detection of mutations in EGFR in circulating lung-cancer cells. The New England journal of medicine. 2008;359:366-77. 30. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2004;350:2129-39. 31. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23:2493-501. 32. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research. 2006;12:6494-501. 33. Daub H, Specht K, Ullrich A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nature reviews Drug discovery. 2004;3:1001-10. 34. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2005;352:786-92. 35. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:2070-5. 36. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer discovery. 2012;2:922-33. 37. Cerny T, Barnes DM, Hasleton P, Barber PV, Healy K, Gullick W, et al. Expression of epidermal growth factor receptor (EGF-R) in human lung tumours. British journal of cancer. 1986;54:265-9. 38. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431:525-6. 39. Okudela K, Woo T, Kitamura H. KRAS gene mutations in lung cancer: particulars established and issues unresolved. Pathology international. 2010;60:651-60. 40. Mao C, Qiu LX, Liao RY, Du FB, Ding H, Yang WC, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung cancer (Amsterdam, Netherlands). 2010;69:272-8. 41. Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clinical cancer research. 2007;13:2890-6. 42. Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of clinical oncology. 2005;23:5900-9. 43. Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer research. 2008;68:4971-6. 44. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-6. 45. Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. Journal of clinical oncology. 2009;27:4232-5. 46. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clinical cancer research. 2008;14:4275-83. 47. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450:893-8. 48. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307-10. 49. Vousden KH, Lane DP. p53 in health and disease. Nature reviews Molecular cell biology. 2007;8:275-83. 50. Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nature cell biology. 2009;11:694-704. 51. Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC, Yang PC. Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. Journal of clinical oncology. 2002;20:900-10. 52. Soussi T, Beroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nature reviews Cancer. 2001;1:233-40. 53. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature genetics. 2012;44:852-60. 54. Workman P, Clarke PA. Resisting targeted therapy: fifty ways to leave your EGFR. Cancer cell. 2011;19:437-40. 55. Soria JC, Mok TS, Cappuzzo F, Janne PA. EGFR-mutated oncogene-addicted non-small cell lung cancer: current trends and future prospects. Cancer treatment reviews. 2012;38:416-30. 56. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. The Lancet Oncology. 2011;12:175-80. 57. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer science. 2007;98:1817-24. 58. Zakowski MF, Ladanyi M, Kris MG. EGFR mutations in small-cell lung cancers in patients who have never smoked. The New England journal of medicine. 2006;355:213-5. 59. Dorantes-Heredia R, Ruiz-Morales JM, Cano-Garcia F. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors. Translational lung cancer research. 2016;5:401-12. 60. Kogo M, Shimizu R, Uehara K, Takahashi Y, Kokubo M, Imai Y, et al. Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor. Lung cancer (Amsterdam, Netherlands). 2015;90:364-8. 61. Jukna A, Montanari G, Mengoli MC, Cavazza A, Covi M, Barbieri F, et al. Squamous Cell Carcinoma 'Transformation' Concurrent with Secondary T790M Mutation in Resistant EGFR-Mutated Adenocarcinomas. Journal of thoracic oncology. 2016;11:e49-51. 62. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105-11. 63. Clarke MF, Fuller M. Stem cells and cancer: two faces of eve. Cell. 2006;124:1111-5. 64. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea--a paradigm shift. Cancer research. 2006;66:1883-90; discussion 95-6. 65. Sullivan JP, Minna JD, Shay JW. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer metastasis reviews. 2010;29:61-72. 66. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer cell. 2003;4:181-9. 67. Han X, Li F, Fang Z, Gao Y, Li F, Fang R, et al. Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma. Nature communications. 2014;5:3261. 68. Kwon MC, Proost N, Song JY, Sutherland KD, Zevenhoven J, Berns A. Paracrine signaling between tumor subclones of mouse SCLC: a critical role of ETS transcription factor Pea3 in facilitating metastasis. Genes & development. 2015;29:1587-92. 69. Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B, et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. The American journal of pathology. 2012;180:599-607. 70. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:15545-50. 71. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570-5. 72. van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378:1741-55. 73. Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics. 2012;44:1104-10. 74. Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics. 2012;44:1111-6. 75. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47-53. 76. Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nature communications. 2015;6:6377. 77. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603-7. 78. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Statistical applications in genetics and molecular biology. 2004;3:Article3. 79. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science (New York, NY). 2004;305:1163-7. 80. Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer research. 2009;69:3256-61. 81. Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta pharmaceutica Sinica B. 2015;5:390-401. 82. Kraus AC, Ferber I, Bachmann SO, Specht H, Wimmel A, Gross MW, et al. In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene. 2002;21:8683-95. 83. Belyanskaya LL, Hopkins-Donaldson S, Kurtz S, Simoes-Wust AP, Yousefi S, Simon HU, et al. Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation. International journal of cancer. 2005;117:755-63. 84. Platta CS, Greenblatt DY, Kunnimalaiyaan M, Chen H. The HDAC inhibitor trichostatin A inhibits growth of small cell lung cancer cells. The Journal of surgical research. 2007;142:219-26. 85. Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, et al. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Molecular cancer therapeutics. 2009;8:2221-31. 86. Hubaux R, Vandermeers F, Crisanti MC, Kapoor V, Burny A, Mascaux C, et al. Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy. European journal of cancer (Oxford, England : 1990). 2010;46:1724-34. 87. Pan CH, Chang YF, Lee MS, Wen BC, Ko JC, Liang SK, et al. Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells. BMC cancer. 2016;16:857. 88. Simms E, Gazdar AF, Abrams PG, Minna JD. Growth of human small cell (oat cell) carcinoma of the lung in serum-free growth factor-supplemented medium. Cancer research. 1980;40:4356-63. 89. Oie HK, Russell EK, Carney DN, Gazdar AF. Cell culture methods for the establishment of the NCI series of lung cancer cell lines. Journal of cellular biochemistry Supplement. 1996;24:24-31. 90. Gazdar AF, Gao B, Minna JD. Lung cancer cell lines: Useless artifacts or invaluable tools for medical science? Lung cancer (Amsterdam, Netherlands). 2010;68:309-18. 91. Gazdar AF, Girard L, Lockwood WW, Lam WL, Minna JD. Lung cancer cell lines as tools for biomedical discovery and research. Journal of the National Cancer Institute. 2010;102:1310-21. 92. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609-15. 93. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335-48. 94. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nature medicine. 2009;15:68-74. 95. Kalluri R. The biology and function of fibroblasts in cancer. Nature reviews Cancer. 2016;16:582-98. 96. Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer discovery. 2012;2:798-811. 97. Tsurutani J, West KA, Sayyah J, Gills JJ, Dennis PA. Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer research. 2005;65:8423-32. 98. Marinov M, Ziogas A, Pardo OE, Tan LT, Dhillon T, Mauri FA, et al. AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15:1277-87. 99. Cardnell RJ, Feng Y, Mukherjee S, Diao L, Tong P, Stewart CA, et al. Activation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer. PloS one. 2016;11:e0152584. 100. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nature reviews Molecular cell biology. 2014;15:178-96. 101. Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;166:21-45. 102. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature reviews Cancer. 2009;9:265-73. 103. Shibue T, Weinberg RA. Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Seminars in cancer biology. 2011;21:99-106. 104. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nature reviews Molecular cell biology. 2006;7:131-42. 105. Krohn A, Ahrens T, Yalcin A, Plones T, Wehrle J, Taromi S, et al. Tumor cell heterogeneity in Small Cell Lung Cancer (SCLC): phenotypical and functional differences associated with Epithelial-Mesenchymal Transition (EMT) and DNA methylation changes. PloS one. 2014;9:e100249. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20423 | - |
dc.description.abstract | Transformation to small cell lung cancer (SCLC) is one of mechanisms for acquired resistance to Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) therapy in lung adenocarcinoma. Approximately 5% of patients with EGFR activating mutations acquire EGFR-TKIs resistance through SCLC transformation. However, the molecular basis of EGFR mutant SCLC transformed from adenocarcinoma was remains unclear. Therefore, we established two EGFR mutant SCLC cell lines from the patients who had EGFR activating mutations and received EGFR-TKIs. Interestingly, both cell lines have two different morphologies, suspended and attached types. Comparative genomic hybridization (CGH) analysis revealed that both type of each cell lines shared the same genomic alterations. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in attached cells. Further, attached cells had lower colony forming ability but exhibited promoting colony forming ability to suspended type cells. Principal component analysis (PCA) and Hierarchical clustering analysis of genome wide RNA expression revealed that EGFR mutant SCLC cells display a unique gene expression pattern distinctly different from NSCLC and classical SCLC cells. Finally, the cell viability of EGFR mutant SCLC cells was strongly inhibited by histone deacetylase (HDAC) inhibitor FK-228(Ropmidepsin). This finding provides a clue for developing therapeutic strategy to overcome EGFR TKI resistance by SCLC transformation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:48:13Z (GMT). No. of bitstreams: 1 ntu-106-D98424001-1.pdf: 4216257 bytes, checksum: 45c84e4c123442103f961830bbf951b3 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 口試委員會審定書………………………………………………..……………………………………………….….i
誌謝…………………………………………………………..………………………………………….…….………....…ii 中文摘要…………………………………………………………..………………………………………..…….…...…iii 英文摘要……………………………………………………………………………………………..……………….….. iv A. Introduction………………………………………………………….………………1 1. Lung cancer…………………………………………………………………….2 2. Histological classification……………………………………………………...3 3. Genetic alteration in lung cancer………………………………………………5 4. EGFR-TKI treatment and drug resistance…………………………………......9 5. EGFR-TKI resistance through SCLC transformation………………..……....10 B. Materials and Methods…………………………………………………………..…12 1. Patients sample collection………………………………………………..…...12 2. Primary culture from malignant pleural effusion of lung cancer…………..…12 3. Cell culture…………………………………………………………….….......13 4. Flow cytometry………………………………………………………………..13 5. Genomic DNA and total RNA extraction…………………………..…………13 6. Comparative genomic hybridization analysis……………………………..…..14 7. Proliferation assay……………………………………………….……………14 8. Invasion assay……………………………………………………….…….…..14 9. Colony formation assay…………………………………….…………………15 10. Quantitative real-time RT-PCR………………………………….……..……..16 11. Condition medium collection…………………………………………………16 12. Western blotting……………………………………………………………….16 13. Rb1 and TP53sequencing……………………………………………………..17 14. Microarray and pathway analysis…………………………………….……….17 15. Principal component analysis and hierarchical clustering…………………….18 16. Growth inhibition assay……………………………………………………….19 17. Kinase assay……………………………………………………………..……19 18. In vivo mouse model………………………………………………………….19 19. Gene set enrichment analysis…………………………………………………20 C. Results……………………………………………………………………………...21 EGFR mutant SCLC cell lines derived from Patients……………………………...21 EGFR mutant SCLC display distinct phenotype………………………………..….21 The functional characterization of suspension and adherent cells…………………22 RB and TP53 loss in EGFR mutant SCLC…………………………………..……..23 Molecular basis of EGFR mutant SCLC……………………………….……..……24 Akt activation in EGFR mutant SCLC………………………………….…….……25 EGFR mutant SCLC are highly sensitive to HDAC 1/2 inhibitor…………………26 D. Dissusion……………………………………………………………………..…….28 E. Figures……………………………………………………………………...………33 F. Tables……………………………………………………………………………….66 G. References………………………………………………………………………….69 | |
dc.language.iso | en | |
dc.title | 上皮生長因子接受器突變之小細胞肺癌細胞間異性授予存活優勢 | zh_TW |
dc.title | Cellular heterogeneity confers survival benefit of small cell lung cancer harboring EGFR mutation | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 何肇基 | |
dc.contributor.oralexamcommittee | 楊慕華,陳健尉,蘇剛毅,華國泰 | |
dc.subject.keyword | 小細胞肺癌,肺腺癌,表皮生長因子接受器,抗藥性,組織蛋白去乙醯?, | zh_TW |
dc.subject.keyword | Small cell lung cancer,lung adenocarcinoma,Epidermal growth factor receptor (EGFR),TKI-resistance,histone deacetylase (HDAC), | en |
dc.relation.page | 85 | |
dc.identifier.doi | 10.6342/NTU201704005 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 4.12 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。