Nimotuzumab, an EGFR‑targeted antibody, promotes radiosensitivity of recurrent esophageal squamous cell carcinoma

Yu,Yang; Guan,Hui; Jiang,Liyang; Li,Xiaolin; Xing,Ligang; Sun,Xiaorong

doi:10.3892/ijo.2020.4981

Nimotuzumab, an EGFR‑targeted antibody, promotes radiosensitivity of recurrent esophageal squamous cell carcinoma

Authors:
- Yang Yu
- Hui Guan
- Liyang Jiang
- Xiaolin Li
- Ligang Xing
- Xiaorong Sun
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Affiliations: School of Medicine and Life Sciences, Shandong Academy of Medical Sciences, University of Jinan, Jinan, Shandong 250031, P.R. China, Department of Radiation Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China, Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China, Department of Nuclear Medicine, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
Published online on: February 12, 2020 https://doi.org/10.3892/ijo.2020.4981
Pages: 945-956

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Abstract

Local tumor recurrence is one of the main causes for the failure of esophageal cancer treatment following radiotherapy. Previous studies have demonstrated that epidermal growth factor receptor (EGFR)‑targeted therapy combined with radiotherapy is expected to become an effective means to control tumor recurrence. The aim of the present study was to investigate the effect and mechanism of nimotuzumab (an EGFR‑targeted antibody) in the treatment of recurrent esophageal carcinoma. The radiation responses of two esophageal squamous carcinoma cell lines, EC109 and TE‑1, with or without nimotuzumab, were first evaluated by CCK‑8 assay. Colony formation and apoptosis were used to measure anti‑proliferation effects. It was demonstrated that nimotuzumab arrested the cell cycle at the G2 phase in vitro. Western blotting and immunofluorescence analysis were used to determine signaling pathway changes. It was observed that nimotuzumab inhibited phosphorylation of EGFR in EC109 cells. Furthermore, recurrent tumor models were established and it was identified that the degree of tumor hypoxia was positively associated with EGFR overexpression. In EC109 cell xenografts, nimotuzumab combined with radiation led to a significant delay in recurrent tumor growth compared with that of radiation alone (P<0.001 for 0 Gy pre‑irradiation, P=0.005 for 20 Gy pre‑irradiation, P=0.005 for 10 Gy pre‑irradiation). These results suggest that nimotuzumab combined with radiation may be an effective means to control recurrent esophageal squamous cell carcinoma with EGFR overexpression.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M and Are C: Global trends in esophageal cancer. J Surg Oncol. 115:564–579. 2017. View Article : Google Scholar : PubMed/NCBI
3	Jha N, Harris J, Seikaly H, Jacobs JR, McEwan AJ and Robbins KT: A phase II study of submandibular gland transfer prior to radiation for prevention of radiation-induced xerostomia in head-and-neck cancer (RTOG 0244). Int J Radiat Oncol Biol Phys. 84:437–442. 2012. View Article : Google Scholar : PubMed/NCBI
4	Brown JM: Tumor hypoxia in cancer therapy. Methods Enzymol. 435:297–321. 2007.PubMed/NCBI
5	Hengstler JG, Bockamp EO, Hermes M, Brulport M, Bauer A, Schormann W, Schiffer IB, Hausherr C, Eshkind L, Antunes C, et al: Oncogene-blocking therapies: New insights from conditional mouse tumor models. Curr Cancer Drug Targets. 6:603–612. 2006. View Article : Google Scholar : PubMed/NCBI
6	Lee AWM, Ng WT, Chan JYW, Corry J, Mäkitie A, Mendenhall WM, Rinaldo A, Rodrigo JP, Saba NF, Strojan P, et al: Management of locally recurrent nasopharyngeal carcinoma. Cancer Treat Rev. 79:1018902019. View Article : Google Scholar : PubMed/NCBI
7	Moeller BJ, Cao Y, Li CY and Dewhirst MW: Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell. 5:429–441. 2004. View Article : Google Scholar : PubMed/NCBI
8	Harada H, Itasaka S, Zhu Y, Zeng L, Xie X, Morinibu A, Shinomiya K and Hiraoka M: Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy. Br J Cancer. 100:747–757. 2009. View Article : Google Scholar : PubMed/NCBI
9	Kwong LN, Zou L, Chagani S, Pedamallu CS, Liu M, Jiang S, Protopopov A, Zhang J, Getz G and Chin L: Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma. Cell Rep. 19:1304–1312. 2017. View Article : Google Scholar : PubMed/NCBI
10	Bussink J, van der Kogel AJ and Kaanders JH: Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol. 9:288–296. 2008. View Article : Google Scholar : PubMed/NCBI
11	Nijkamp MM, Hoogsteen IJ, Span PN, Takes RP, Lok J, Rijken PF, van der Kogel AJ, Bussink J and Kaanders JH: Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma. Radiother Oncol. 101:165–170. 2011. View Article : Google Scholar : PubMed/NCBI
12	Harari PM and Huang SM: Combining EGFR inhibitors with radiation or chemotherapy: Will preclinical studies predict clinical results? Int J Radiat Oncol Biol Phys. 58:976–983. 2004. View Article : Google Scholar : PubMed/NCBI
13	Milas L, Fan Z, Andratschke NH and Ang KK: Epidermal growth factor receptor and tumor response to radiation: In vivo preclinical studies. Int J Radiat Oncol Biol Phys. 58:966–971. 2004. View Article : Google Scholar : PubMed/NCBI
14	Giralt J, de las Heras M, Cerezo L, Eraso A, Hermosilla E, Velez D, Lujan J, Espin E, Rosello J, Majó J, et al Grupo Español de Investigacion Clinica en Oncologia Radioterápica (GICOR): The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: A multicenter, retrospective analysis. Radiother Oncol. 74:101–108. 2005. View Article : Google Scholar : PubMed/NCBI
15	Baumann M, Krause M, Dikomey E, Dittmann K, Dörr W, Kasten-Pisula U and Rodemann HP: EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms. Radiother Oncol. 83:238–248. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wang KL, Wu TT, Choi IS, Wang H, Resetkova E and Correa AM: Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer. 109:658–667. 2007. View Article : Google Scholar : PubMed/NCBI
17	Diaz Miqueli A, Rolff J, Lemm M, Fichtner I, Perez R and Montero E: Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies. Br J Cancer. 100:950–958. 2009. View Article : Google Scholar : PubMed/NCBI
18	Akashi Y, Okamoto I, Iwasa T, Yoshida T, Suzuki M, Hatashita E, Yamada Y, Satoh T, Fukuoka M, Ono K, et al: Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer. 98:749–755. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kawaguchi Y, Kono K, Mimura K, Sugai H, Akaike H and Fujii H: Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer. 120:781–787. 2007. View Article : Google Scholar
20	Zhao L, Li QQ, Zhang R, Xi M, Liao YJ, Qian D, He LR, Zeng YX, Xie D and Liu MZ: The overexpression of IGFBP-3 is involved in the chemosensitivity of esophageal squamous cell carcinoma cells to nimotuzumab combined with cisplatin. Tumour Biol. 33:1115–1123. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yu Y, Li X, Xu H, Liu J, Dong M, Yang J, Sun L, Sun X and Xing L: Correlation of hypoxia status with radiosensitizing effects of sodium glycididazole: A preclinical study. Oncol Lett. 15:6481–6488. 2018.PubMed/NCBI
22	Zips D, Eicheler W, Brüchner K, Jackisch T, Geyer P, Petersen C, van der Kogel AJ and Baumann M: Impact of the tumour bed effect on microenvironment, radiobiological hypoxia and the outcome of fractionated radiotherapy of human FaDu squamous-cell carcinoma growing in the nude mouse. Int J Radiat Biol. 77:1185–1193. 2001. View Article : Google Scholar : PubMed/NCBI
23	Chen FH, Chiang CS, Wang CC, Fu SY, Tsai CS, Jung SM, Wen CJ, Lee CC and Hong JH: Vasculatures in tumors growing from preirradiated tissues: Formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Int J Radiat Oncol Biol Phys. 80:1512–1521. 2011. View Article : Google Scholar : PubMed/NCBI
24	Zhao L, He LR, Xi M, Cai MY, Shen JX, Li QQ, Liao YJ, Qian D, Feng ZZ, Zeng YX, et al: Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3. J Transl Med. 10:2492012. View Article : Google Scholar : PubMed/NCBI
25	Baraban E, Sadigh S, Rosenbaum J, Van Arnam J, Bogusz AM, Mehr C and Bagg A: Cyclin D1 expression and novel mutational findings in Rosai-Dorfman disease. Br J Haematol. 186:837–844. 2019. View Article : Google Scholar : PubMed/NCBI
26	Okamoto I: Epidermal growth factor receptor in relation to tumor development: EGFR-targeted anticancer therapy. FEBS J. 277:309–315. 2010. View Article : Google Scholar
27	Li S, Kussie P and Ferguson KM: Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure. 16:216–227. 2008. View Article : Google Scholar : PubMed/NCBI
28	Chakravarti A, Winter K, Wu CL, Kaufman D, Hammond E, Parliament M, Tester W, Hagan M, Grignon D, Heney N, et al: Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: A report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 62:309–317. 2005. View Article : Google Scholar : PubMed/NCBI
29	Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, et al: Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): A multicentre, phase 2/3 randomised trial. Lancet Oncol. 14:627–637. 2013. View Article : Google Scholar : PubMed/NCBI
30	Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, et al: Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial. JAMA Oncol. 3:1520–1528. 2017. View Article : Google Scholar : PubMed/NCBI
31	Lu M, Wang X, Shen L, Jia J, Gong J, Li J, Li J, Li Y, Zhang X, Lu Z, et al: Nimotuzumab plus paclitaxel and cisplatin as the first line treatment for advanced esophageal squamous cell cancer: A single centre prospective phase II trial. Cancer Sci. 107:486–490. 2016. View Article : Google Scholar : PubMed/NCBI
32	Ramos-Suzarte M, Lorenzo-Luaces P, Lazo NG, Perez ML, Soriano JL, Gonzalez CE, Hernadez IM, Albuerne YÁ, Moreno BP, Alvarez ES, et al: Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy. Cancer Biol Ther. 13:600–605. 2012. View Article : Google Scholar : PubMed/NCBI
33	de Castro Junior G, Segalla JG, de Azevedo SJ, Andrade CJ, Grabarz D, de Araújo Lima França B, Del Giglio A, Lazaretti NS, Álvares MN, Pedrini JL, et al: A randomised phase II study of chemoradiotherapy with or without nimotuzumab in locally advanced oesophageal cancer: NICE trial. Eur J Cancer. 88:21–30. 2018. View Article : Google Scholar
34	Cheng JC, Klausen C and Leung PC: Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett. 329:197–206. 2013. View Article : Google Scholar
35	Lin P, Wang W, Cai WJ, Han CR, Sun Y, Li M and Sun BC: Relationship between the expression of hypoxia-inducible factor-1alpha and epidermal growth factor receptor and micro vessel density and their clinical significance. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 44:480–485. 2009.In Chinese. PubMed/NCBI
36	Wouters A, Boeckx C, Vermorken JB, Van den Weyngaert D, Peeters M and Lardon F: The intriguing interplay between therapies targeting the epidermal growth factor receptor, the hypoxic microenvironment and hypoxia-inducible factors. Curr Pharm Des. 19:907–917. 2013. View Article : Google Scholar
37	Peng XH, Karna P, Cao Z, Jiang BH, Zhou M and Yang L: Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 281:25903–25914. 2006. View Article : Google Scholar : PubMed/NCBI
38	Wu P, Liu J, Sun X, Li X, Xing L and Yu J: Enhanced radio-sensitizing by sodium glycididazole in a recurrent esophageal carcinoma tumor model. Oncotarget. 8:63871–63880. 2017.PubMed/NCBI