Xu Zhang, Yuxiang Wang, Linghua Meng. Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1054-1067

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy
Xu Zhanga,b, Yuxiang Wanga, Linghua Menga,b
a. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
b. University of Chinese Academy of Sciences, Beijing 100049, China
Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.
Key words:    Esophageal cancer    Esophageal squamous cell carcinoma    Esophageal adenocarcinoma    Next-generation sequencing    Genomic alteration    Somatic mutation    Copy number variation    Molecularly targeted therapy   
Received: 2021-05-25     Revised: 2021-08-23
DOI: 10.1016/j.apsb.2021.09.028
Funds: This work was supported by National Natural Science Foundation of China (81973345 and 82173832) and "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020111, China).
Corresponding author: Linghua Meng,
Author description:
PDF(KB) Free
Xu Zhang
Yuxiang Wang
Linghua Meng

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-249
[2] Murphy G, McCormack V, Abedi-Ardekani B, Arnold M, Camargo MC, Dar NA, et al. International cancer seminars: a focus on esophageal squamous cell carcinoma. Ann Oncol 2017; 28: 2086-2093
[3] Rubenstein JH, Shaheen NJ. Epidemiology, diagnosis, and management of esophageal adenocarcinoma. Gastroenterology 2015; 149: 302-317 e1
[4] Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet 2013; 381: 400-412
[5] He S, Xu J, Liu X, Zhen Y. Advances and challenges in the treatment of esophageal cancer. Acta Pharm Sin B 2021. Available from:
[6] Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol 2018; 834: 188-196
[7] Alekseyev YO, Fazeli R, Yang S, Basran R, Maher T, Miller NS, et al. A next-generation sequencing primer-how does it work and what can it do?. Acad Pathol 2018; 5: 2374289518766521
[8] Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat 2014; 35: 672-688
[9] England B, Huang TG, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumor Biol 2013; 34: 2063-2074
[10] Kang N, Wang Y, Guo SC, Ou YW, Wang GC, Chen J, et al. Mutant TP53 G245C and R273H promote cellular malignancy in esophageal squamous cell carcinoma. BMC Cell Biol 2018; 19: 16
[11] Huang MR, Jin JY, Zhang FR, Wu YX, Xu CY, Ying LS, et al. Non-disruptive mutation in TP53 DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma. Ann Transl Med 2020; 8: 316
[12] Stachler MD, Camarda ND, Deitrick C, Kim A, Agoston AT, Odze RD, et al. Detection of mutations in Barrett's esophagus before progression to high-grade dysplasia or adenocarcinoma. Gastroenterology 2018; 155: 156-167
[13] Witcher M, Emerson BM. Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell 2009; 34: 271-284
[14] Cheng CX, Zhou Y, Li HY, Xiong T, Li SC, Bi YH, et al. Whole-genome sequencing reveals diverse models of structural variations in esophageal squamous cell carcinoma. Am J Hum Genet 2016; 98: 256-274
[15] Smeds J, Berggren P, Ma X, Xu Z, Hemminki K, Kumar R. Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF)) and p53 genes are major targets for inactivation. Carcinogenesis 2002; 23: 645-655
[16] Stachler MD, Taylor-Weiner A, Peng SY, McKenna A, Agoston AT, Odze RD, et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat Genet 2015; 47: 1047-1055
[17] Bian YS, Osterheld MC, Fontolliet C, Bosman FT, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus. Gastroenterology 2002; 122: 1113-1121
[18] Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012; 151: 56-67
[19] Lu SH, Hsieh LL, Luo FC, Weinstein IB. Amplification of the EGF receptor and c-myc genes in human esophageal cancers. Int J Cancer 1988; 42: 502-505
[20] Wang W, Xue L, Wang P. Prognostic value of beta-catenin, c-myc, and cyclin D1 expressions in patients with esophageal squamous cell carcinoma. Med Oncol 2011; 28: 163-169
[21] von Rahden BH, Stein HJ, Puhringer-Oppermann F, Sarbia M. c-myc amplification is frequent in esophageal adenocarcinoma and correlated with the upregulation of VEGF-A expression. Neoplasia 2006; 8: 702-707
[22] Fagan RJ, Dingwall AK. COMPASS ascending: emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer. Cancer Lett 2019; 458: 56-65
[23] Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, et al. Genetic landscape of esophageal squamous cell carcinoma. Nat Genet 2014; 46: 1097-1102
[24] Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 2014; 509: 91-95
[25] Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 2005; 16: 139-149
[26] Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010; 10: 116-129
[27] Arai H, Ueno T, Tangoku A, Yoshino S, Abe T, Kawauchi S, et al. Detection of amplified oncogenes by genome DNA microarrays in human primary esophageal squamous cell carcinoma: comparison with conventional comparative genomic hybridization analysis. Cancer Genet Cytogen 2003; 146: 16-21
[28] Salem ME, Puccini A, Xiu J, Raghavan D, Lenz HJ, Korn WM, et al. Comparative molecular analyses of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. Oncologist 2018; 23: 1319-1327
[29] Shimada Y, Okumura T, Takei Y, Watanabe K, Nagata T, Hori T, et al. Role of fibroblast growth factor receptors in esophageal squamous cell carcinoma. Esophagus 2015; 13: 30-41
[30] Takei Y, Matsumura T, Watanabe K, Nakamine H, Sudo T, Shimizu K, et al. FGFRL1 deficiency reduces motility and tumorigenic potential of cells derived from oesophageal squamous cell carcinomas. Oncol Lett 2018; 16: 809-814
[31] Song Q, Liu Y, Jiang D, Wang H, Huang J, Xu Y, et al. High amplification of FGFR1 gene is a delayed poor prognostic factor in early stage ESCC patients. Oncotarget 2017; 8: 74539-74553
[32] Wang D, Du L, Wang Z, Liu X, Qin Y, Wang Q, et al. Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma. Oncotarget 2017; 8: 88857-88869
[33] Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004; 59: 21-26
[34] Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005; 23: 2445-2459
[35] Hanawa M, Suzuki S, Dobashi Y, Yamane T, Kono K, Enomoto N, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 2006; 118: 1173-1180
[36] Zhang W, Zhu H, Liu X, Wang Q, Zhang X, He J, et al. Epidermal growth factor receptor is a prognosis predictor in patients with esophageal squamous cell carcinoma. Ann Thorac Surg 2014; 98: 513-519
[37] Cao HH, Zheng CP, Wang SH, Wu JY, Shen JH, Xu XE, et al. A molecular prognostic model predicts esophageal squamous cell carcinoma prognosis. PLoS One 2014; 9: e106007
[38] Guo LX, Zhang T, Xiong Y, Yang YA. Roles of NOTCH1 as a therapeutic target and a biomarker for lung cancer: controversies and perspectives. Dis Markers 2015; 2015: 520590
[39] Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood 2017; 129: 1113-1123
[40] Efstratiadis A, Szabolcs M, Klinakis A. Notch, Myc and breast cancer. Cell Cycle 2007; 6: 418-429
[41] Li Y, Li Y, Chen X. NOTCH and esophageal squamous cell carcinoma. Adv Exp Med Biol 2021; 1287: 59-68
[42] Sawangarun W, Mandasari M, Aida J, Morita KI, Kayamori K, Ikeda T, et al. Loss of Notch1 predisposes oro-esophageal epithelium to tumorigenesis. Exp Cell Res 2018; 372: 129-140
[43] Lu ZM, Liu HT, Xue LX, Xu PR, Gong TX, Hou GQ. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706. Int J Oncol 2008; 32: 643-651
[44] Song B, Cui HY, Li YP, Cheng CX, Yang B, Wang F, et al. Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China. Oncotarget 2016; 7: 3599-3613
[45] Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501
[46] Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30: 193-204
[47] Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 2014; 46: 467-473
[48] Akagi. Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma. Int J Oncology 2009; 34: 767-775
[49] Kim HS, Lee SE, Bae YS, Kim DJ, Lee CG, Hur J, et al. PIK3CA amplification is associated with poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Oncotarget 2016; 7: 30691-30701
[50] Wang L, Shan L, Zhang S, Ying J, Xue L, Yuan Y, et al. PIK3CA gene mutations and overexpression: implications for prognostic biomarker and therapeutic target in Chinese esophageal squamous cell carcinoma. PLoS One 2014; 9: e103021
[51] Gu F, Pfeiffer RM, Bhattacharjee S, Han SS, Taylor PR, Berndt S, et al. Common genetic variants in the 9p21 region and their associations with multiple tumours. Br J Cancer 2013; 108: 1378-1386
[52] Lin X, Yan C, Gao Y, Du J, Zhu X, Yu F, et al. Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Sci 2017; 108: 250-255
[53] Chen J, Guo L, Peiffer DA, Zhou L, Chan OT, Bibikova M, et al. Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int J Cancer 2008; 122: 2249-2254
[54] Shen TY, Mei LL, Qiu YT, Shi ZZ. Identification of candidate target genes of genomic aberrations in esophageal squamous cell carcinoma. Oncol Lett 2016; 12: 2956-2961
[55] Su D, Zhang D, Jin J, Ying L, Han M, Chen K, et al. Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma. Nat Commun 2019; 10: 5076
[56] Donnellan R, Chetty R. Cyclin D1 and human neoplasia. J Clinical Pathol-Mol Pathol 1998; 51: 1-7
[57] Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y, et al. Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology 2016; 150: 1171-1182
[58] Sunpaweravong P, Sunpaweravong S, Puttawibul P, Mitarnun W, Zeng C, Baron AE, et al. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 2005; 131: 111-119
[59] Hou X, Liang RB, Wei JC, Xu Y, Fu JH, Luo RZ, et al. Cyclin D1 expression predicts postoperative distant metastasis and survival in resectable esophageal squamous cell carcinoma. Oncotarget 2016; 7: 31088-31096
[60] Froimchuk E, Jang Y, Ge K. Histone H3 lysine 4 methyltransferase KMT2D. Gene 2017; 627: 337-342
[61] Dai W, Ko JMY, Choi SSA, Yu Z, Ning L, Zheng H, et al. Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma. J Pathol 2017; 242: 500-510
[62] Kerins MJ, Ooi A. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci Rep 2018; 8: 12846
[63] Kim YR, Oh JE, Kim MS, Kang MR, Park SW, Han JY, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol 2010; 220: 446-451
[64] Cui Y, Chen H, Xi R, Cui H, Zhao Y, Xu E, et al. Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma. Cell Res 2020; 30: 902-913
[65] Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K, et al. NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 2011; 13: 864-873
[66] Ma S, Paiboonrungruan C, Yan T, Williams KP, Major MB, Chen XL. Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target. Ann N Y Acad Sci 2018; 1434: 164-172
[67] Garrett TPJ, McKern NM, Lou MZ, Elleman TC, Adams TE, Lovrecz GO, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003; 11: 495-505
[68] GrausPorta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16: 1647-1655
[69] Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, et al. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61-70
[70] Oh DY, Bang YJ. HER2-targeted therapies-a role beyond breast cancer. Nat Rev Clin Oncol 2020; 17: 33-48
[71] Wang K, Johnson A, Au SM, Klempner SJ, Bekaii-Saab T, Vacirca JL, et al. Comprehensive genomic profiling of advanced esophageal squamous cell carcinomas and esophageal adenocarcinomas reveals similarities and differences. Oncologist 2015; 20: 1132-1139
[72] Plum PS, Gebauer F, Kramer M, Alakus H, Berlth F, Chon SH, et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer 2019; 19: 38
[73] Realdon S, Dassie E, Fassan M, Dall'Olmo L, Hatem G, Buda A, et al. In vivo molecular imaging of HER2 expression in a rat model of Barrett's esophagus adenocarcinoma. Dis Esophagus 2015; 28: 394-403
[74] Yoon HH, Shi Q, Sukov WR, Wiktor AE, Khan M, Sattler CA, et al. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin Cancer Res 2012; 18: 546-554
[75] Yoon HH, Sukov WR, Shi Q, Sattler CA, Wiktor AE, Diasio RB, et al. HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma. Cancer 2014; 120: 415-424
[76] Griffiths EA, Pritchard SA, McGrath SM, Valentine HR, Price PM, Welch IM, et al. Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. Br J Cancer 2007; 96: 1377-1383
[77] Carraro A, Trevellin E, Fassan M, Kotsafti A, Lunardi F, Porzionato A, et al. Esophageal adenocarcinoma microenvironment: peritumoral adipose tissue effects associated with chemoresistance. Cancer Sci 2017; 108: 2393-2404
[78] de Gouw D, Rijpkema M, de Bitter TJJ, Baart VM, Sier CFM, Hernot S, et al. Identifying biomarkers in lymph node metastases of esophageal adenocarcinoma for tumor-targeted imaging. Mol Diagn Ther 2020; 24: 191-200
[79] Prins MJ, Verhage RJ, ten Kate FJ, van Hillegersberg R. Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. J Gastrointest Surg 2012; 16: 956-966
[80] Jancik S, Drabek J, Radzioch D, Hajduch M. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol 2010; 2010: 150960
[81] Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B 2019; 9: 871-879
[82] Nones K, Waddell N, Wayte N, Patch AM, Bailey P, Newell F, et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat Commun 2014; 5: 5224
[83] Essakly A, Loeser H, Kraemer M, Alakus H, Chon SH, Zander T, et al. PIK3CA and KRAS amplification in esophageal adenocarcinoma and their impact on the inflammatory tumor microenvironment and prognosis. Transl Oncol 2020; 13: 157-164
[84] Wu RC, Wang TL, Shih Ie M. The emerging roles of ARID1A in tumor suppression. Cancer Biol Ther 2014; 15: 655-664
[85] Drage MG, Tippayawong M, Agoston AT, Zheng Y, Bueno R, Hornick JL, et al. Morphological features and prognostic significance of ARID1A-deficient esophageal adenocarcinomas. Arch Pathol Lab Med 2017; 141: 970-977
[86] Streppel MM, Lata S, DelaBastide M, Montgomery EA, Wang JS, Canto MI, et al. Next-generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-suppressor gene in Barrett's esophagus. Oncogene 2014; 33: 347-357
[87] Schallenberg S, Bork J, Essakly A, Alakus H, Buettner R, Hillmer AM, et al. Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma. BMC Cancer 2020; 20: 12
[88] Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, et al. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc Natl Acad Sci U S A 2010; 107: 11026-11031
[89] Herrera LJ, El-Hefnawy T, Queiroz de Oliveira PE, Raja S, Finkelstein S, Gooding W, et al. The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma. Neoplasia 2005; 7: 75-84
[90] Wang Y, Jiang Z, Xu C, Wang H, Tan L, Su J, et al. Increased MET gene copy number negatively affects the survival of esophageal squamous cell carcinoma patients. BMC Cancer 2019; 19: 240
[91] Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011; 29: 4803-4810
[92] Strickler JH, LoRusso P, Salgia R, Kang YK, Yen CJ, Lin CC, et al. Phase I dose-escalation and -expansion study of Telisotuzumab (ABT-700), an anti-c-Met antibody, in patients with advanced solid tumors. Mol Cancer Ther 2020; 19: 1210-1217
[93] Hong DS, LoRusso P, Hamid O, Janku F, Kittaneh M, Catenacci DVT, et al. Phase I study of AMG 337, a highly selective small-molecule MET inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2019; 25: 2403-2413
[94] Van Cutsem E, Karaszewska B, Kang YK, Chung HC, Shankaran V, Siena S, et al. A multicenter phase II study of AMG 337 in patients with MET-amplified gastric/gastroesophageal junction/esophageal adenocarcinoma and other MET-amplified solid tumors. Clin Cancer Res 2019; 25: 2414-2423
[95] Kosovec JE, Zaidi AH, Omstead AN, Matsui D, Biedka MJ, Cox EJ, et al. CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease. Oncotarget 2017; 8: 100421-100432
[96] Ou HL, Schumacher B. DNA damage responses and p53 in the aging process. Blood 2018; 131: 488-495
[97] Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen L, Razak AR, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol 2016; 34: 4371-4380
[98] Ohashi S, Kikuchi O, Nakai Y, Ida T, Saito T, Kondo Y, et al. Synthetic lethality with trifluridine/tipiracil and checkpoint kinase 1 inhibitor for esophageal squamous cell carcinoma. Mol Cancer Ther 2020; 19: 1363-1372
[99] Schneider BJ, Shah MA, Klute K, Ocean A, Popa E, Altorki N, et al. Phase I study of epigenetic priming with azacitidine prior to standard neoadjuvant chemotherapy for patients with resectable gastric and esophageal adenocarcinoma: evidence of tumor hypomethylation as an indicator of major histopathologic response. Clin Cancer Res 2017; 23: 2673-2680
[100] Ahrens TD, Timme S, Hoeppner J, Ostendorp J, Hembach S, Follo M, et al. Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and azacytidine. Epigenetics 2015; 10: 431-445
[101] Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol 2019; 5: 546-550
[102] Zhang B, Qi L, Wang X, Xu J, Liu Y, Mu L, et al. Phase II clinical trial using camrelizumab combined with apatinib and chemotherapy as the first-line treatment of advanced esophageal squamous cell carcinoma. Cancer Commun 2020; 40: 711-720
[103] Wang X, Zhang B, Chen X, Mo H, Wu D, Lan B, et al. Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody. Thorac Cancer 2019; 10: 1395-1401
[104] Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, et al. KEYNOTE-975 study design: a phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future Oncol 2021; 17: 1143-1153
[105] Kato H, Arao T, Matsumoto K, Fujita Y, Kimura H, Hayashi H, et al. Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma. Int J Oncol 2013; 42: 1151-1158
[106] Hara F, Aoe M, Doihara H, Taira N, Shien T, Takahashi H, et al. Antitumor effect of gefitinib (‘Iressa’) on esophageal squamous cell carcinoma cell lines in vitro and in vivo. Cancer Lett 2005; 226: 37-47
[107] Teraishi F, Kagawa S, Watanabe T, Tango Y, Kawashima T, Umeoka T, et al. ZD1839 (gefitinib, ‘Iressa’), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma. FEBS Lett 2005; 579: 4069-4075
[108] Mimura K, Kono K, Maruyama T, Watanabe M, Izawa S, Shiba S, et al. Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. Int J Cancer 2011; 129: 2408-2416
[109] Hou W, Qin X, Zhu X, Fei M, Liu P, Liu L, et al. Lapatinib inhibits the growth of esophageal squamous cell carcinoma and synergistically interacts with 5-fluorouracil in patient-derived xenograft models. Oncol Rep 2013; 30: 707-714
[110] Zhao L, He LR, Xi MA, Cai MY, Shen JX, Li QQ, et al. Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3. J Transl Med 2012; 10: 249
[111] Zhu H, Wang C, Wang J, Chen D, Deng J, Deng J, et al. A subset of esophageal squamous cell carcinoma patient-derived xenografts respond to cetuximab, which is predicted by high EGFR expression and amplification. J Thorac Dis 2018; 10: 5328-5338
[112] Li G, Hu W, Wang J, Deng X, Zhang P, Zhang X, et al. Phase II study of concurrent chemoradiation in combination with erlotinib for locally advanced esophageal carcinoma. Int J Radiat Oncol Biol Phys 2010; 78: 1407-1412
[113] Zhao CH, Lin L, Liu JZ, Liu RR, Chen YL, Ge FJ, et al. A phase II study of concurrent chemoradiotherapy and erlotinib for inoperable esophageal squamous cell carcinoma. Oncotarget 2016; 7: 57310-57316
[114] Xie C, Jing Z, Luo H, Jiang W, Ma L, Hu W, et al. Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial. Br J Cancer 2020; 123: 1616-1624
[115] Huang J, Fan Q, Lu P, Ying J, Ma C, Liu W, et al. Icotinib in patients with pretreated advanced esophageal squamous cell carcinoma with EGFR overexpression or EGFR gene amplification: a single-arm, multicenter phase 2 study. J Thorac Oncol 2016; 11: 910-917
[116] Luo H, Jiang W, Ma L, Chen P, Fang M, Ding L, et al. Icotinib with concurrent radiotherapy vs radiotherapy alone in older adults with unresectable esophageal squamous cell carcinoma: a phase II randomized clinical trial. JAMA Netw Open 2020; 3: e2019440
[117] Xu YP, Zheng YD, Sun XJ, Yu XM, Gu JL, Wu W, et al. Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: preliminary results of a phase II study. Oncotarget 2015; 6: 38429-38439
[118] Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 2012; 18: 1855-1862
[119] Xin Z, Song X, Jiang B, Gongsun X, Song L, Qin Q, et al. Blocking FGFR4 exerts distinct anti-tumorigenic effects in esophageal squamous cell carcinoma. Thorac Cancer 2018; 9: 1687-1698
[120] Luo H, Quan J, Xiao H, Luo J, Zhang Q, Pi G, et al. FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial-mesenchymal transition to gefitinib. Oncol Rep 2018; 39: 2270-2278
[121] Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, et al. AXL mediates resistance to PI3K alpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell 2015; 27: 533-546
[122] Xiang HY, Wang X, Chen YH, Zhang X, Tan C, Wang Y, et al. Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors. Eur J Med Chem 2021; 209: 112913
[123] Shi JJ, Xing H, Wang YX, Zhang X, Zhan QM, Geng MY, et al. PI3Kalpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment. Cancer Lett 2019; 459: 145-155
[124] Badarni M, Prasad M, Balaban N, Zorea J, Yegodayev KM, Joshua BZ, et al. Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy. JCI Insight 2019; 5: e125341
[125] Wang YX, Zhang X, Ma QY, Hu LD, Zhang X, Wang Y, et al. Adaptive resistance to PI3Kalpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells. Cell Death Dis 2021; 12: 85
[126] Nusse R, Clevers H. Wnt/beta-Catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169: 985-999
[127] Bugter JM, Fenderico N, Maurice MM. Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat Rev Cancer 2021; 21: 5-21
[128] Hasan MR, Saraya A, Gupta SD, Chauhan SS, Ralhan R. Wnt signaling protein expression based pridiction of recurrent free survival in esophageal cancer. Gastroenterology 2017; 152: S1030-S1031
[129] Zhao Y, Yi J, Tao L, Huang G, Chu X, Song H, et al. Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma. Cell Death Dis 2018; 9: 433
[130] Xu Z, Xu X, O'Laoi R, Ma H, Zheng J, Chen S, et al. Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the ‘reversed’ amide scaffold. Bioorg Med Chem 2016; 24: 5861-5872
[131] Bang YJ, Van Cutsem E, Feyereislova A, To GATI. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (TOGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687-697
[132] Smyth EC, Rowley S, Cafferty FH, Allum W, Grabsch HI, Stenning S, et al. Safety and efficacy of the addition of lapatinib to perioperative chemotherapy for resectable HER2-positive gastroesophageal adenocarcinoma: a randomized phase 2 clinical trial. JAMA Oncol 2019; 5: 1181-1187
[133] Stroes CI, Schokker S, Creemers A, Molenaar RJ, Hulshof M, van der Woude SO, et al. Phase II feasibility and biomarker study of neoadjuvant trastuzumab and pertuzumab with chemoradiotherapy for resectable human epidermal growth factor receptor 2-positive esophageal adenocarcinoma: TRAP study. J Clin Oncol 2020; 38: 462-471
[134] Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383: 31-39
[135] Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15: 1224-1235
[136] Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006; 24: 5201-5206
[137] Yanwei L, Feng H, Ren P, Yue J, Zhang W, Tang P, et al. Safety and efficacy of apatinib monotherapy for unresectable, metastatic esophageal cancer: a single-arm, open-label, phase II study. Oncologist 2020; 25: e1464-e1472
Similar articles:
1.Shiming He, Jian Xu, Xiujun Liu, Yongsu Zhen.Advances and challenges in the treatment of esophageal cancer[J]. Acta Pharmaceutica Sinica B, 2021,11(11): 3379-3392
Similar articles: