Synergistic antitumor effect of the anti‑ErbB2 antibodies trastuzumab and H2‑18 on trastuzumab‑resistant gastric cancer cells

Wang,Chao; Wang,Lingfei; Liang,Beibei; Zhou,Bo; Sun,Yu; Meng,Yanchun; Dong,Jian; Chen,Lin; Li,Bohua

doi:10.3892/ol.2021.12661

Synergistic antitumor effect of the anti‑ErbB2 antibodies trastuzumab and H2‑18 on trastuzumab‑resistant gastric cancer cells

Authors:
- Chao Wang
- Lingfei Wang
- Beibei Liang
- Bo Zhou
- Yu Sun
- Yanchun Meng
- Jian Dong
- Lin Chen
- Bohua Li
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Affiliations: Department of Cell Biology, Navy Medical University (The Second Military Medical University), Shanghai 200433, P.R. China, Department of Oncology, The 903rd Hospital of The Chinese People's Liberation Army, Hangzhou, Zhejiang 310013, P.R. China, School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, Basic Medicine Faculty, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, P.R. China, Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Colorectal Surgery, Affiliated to The Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China
Published online on: March 18, 2021 https://doi.org/10.3892/ol.2021.12661
Article Number: 400
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Trastuzumab resistance is a severe problem in the treatment of ErbB2‑amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2‑overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2‑18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2‑18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab‑sensitive gastric cancer cell line, NCI‑N87 and the trastuzumab‑resistant gastric cancer cell line, NCI‑N87‑TraRT. Furthermore, H2‑18 plus trastuzumab inhibited the growth of NCI‑N87‑TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2‑18 plus trastuzumab had a potent ability to inhibit NCI‑N87‑TraRT cells to form colonies. Notably, H2‑18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2‑18 plus trastuzumab effectively inhibited the growth of both NCI‑N87 and NCI‑N87‑TraRT xenograft tumors. Further experiments revealed that in NCI‑N87‑TraRT cells, H2‑18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p‑)HER3, p‑AKT and p‑ERK. However, compared with trastuzumab plus pertuzumab, H2‑18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c‑jun in NCI‑N87‑TraRT cells. Therefore, the superior antitumor efficacy of H2‑18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death‑inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2‑18, trastuzumab and pertuzumab were further investigated. The results revealed that H2‑18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti‑ErbB2 monoclonal antibody combinations tested. In summary, H2‑18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2‑amplified gastric cancer cell lines.

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1	Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 235:177–182. 1987. View Article : Google Scholar : PubMed/NCBI
2	Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and Press MF: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 244:707–712. 1989. View Article : Google Scholar : PubMed/NCBI
3	Thiel A and Ristimaki A: Targeted therapy in gastric cancer. APMIS. 123:365–372. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al: 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. 376:687–697. 2010. View Article : Google Scholar : PubMed/NCBI
5	Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A and Arnold D: Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 27:v38–v49. 2016. View Article : Google Scholar : PubMed/NCBI
6	Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 20:719–726. 2002. View Article : Google Scholar : PubMed/NCBI
7	Nahta R and Esteva FJ: HER2 therapy: Molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 8:2152006. View Article : Google Scholar : PubMed/NCBI
8	Nahta R, Yu D, Hung MC, Hortobagyi GN and Esteva FJ: Mechanisms of disease: Understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 3:269–280. 2006. View Article : Google Scholar : PubMed/NCBI
9	Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 28:1138–1144. 2010. View Article : Google Scholar : PubMed/NCBI
10	Cortes J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, Verma S, Albanell J, Conte P, Lluch A, et al: Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: Activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 30:1594–1600. 2012. View Article : Google Scholar : PubMed/NCBI
11	Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, et al: Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 28:1124–1130. 2010. View Article : Google Scholar : PubMed/NCBI
12	von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, et al: Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: A german breast group 26/breast international group 03–05 study. J Clin Oncol. 27:1999–2006. 2009. View Article : Google Scholar : PubMed/NCBI
13	Wang C, Wang L, Yu X, Zhang Y, Meng Y, Wang H, Yang Y, Gao J, Wei H, Zhao J, et al: Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody. Oncotarget. 8:42742–42751. 2017. View Article : Google Scholar : PubMed/NCBI
14	Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, et al: Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2:127–137. 2002. View Article : Google Scholar : PubMed/NCBI
15	Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D and Sliwkowski MX: Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 15:429–440. 2009. View Article : Google Scholar : PubMed/NCBI
16	Nahta R, Hung MC and Esteva FJ: The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 64:2343–2346. 2004. View Article : Google Scholar : PubMed/NCBI
17	Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J and Hasmann M: Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69:9330–9336. 2009. View Article : Google Scholar : PubMed/NCBI
18	Lu Q, Wang L, Zhang Y, Yu X, Wang C, Wang H, Yang Y, Chong X, Xia T, Meng Y, et al: An anti-ErbB2 fully human antibody circumvents trastuzumab resistance. Oncotarget. 7:67129–76141. 2016. View Article : Google Scholar : PubMed/NCBI
19	Li B, Meng Y, Zheng L, Zhang X, Tong Q, Tan W, Hu S, Li H, Chen Y, Song J, et al: Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization. Cancer Res. 73:6471–6483. 2013. View Article : Google Scholar : PubMed/NCBI
20	Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K and Sliwkowski MX: Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 55:717–727. 2006. View Article : Google Scholar : PubMed/NCBI
21	Li B, Shi S, Qian W, Zhao L, Zhang D, Hou S, Zheng L, Dai J, Zhao J, Wang H and Guo Y: Development of novel tetravalent anti-CD20 antibodies with potent antitumor activity. Cancer Res. 68:2400–2408. 2008. View Article : Google Scholar : PubMed/NCBI
22	Li B, Zhao L, Guo H, Wang C, Zhang X, Wu L, Chen L, Tong Q, Qian W, Wang H and Guo Y: Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma. Blood. 114:5007–5015. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zhang X, Chen J, Weng Z, Li Q, Zhao L, Yu N, Deng L, Xu W, Yang Y, Zhu Z, et al: A new anti-HER2 antibody that enhances the anti-tumor efficacy of trastuzumab and pertuzumab with a distinct mechanism of action. Mol Immunol. 119:48–58. 2020. View Article : Google Scholar : PubMed/NCBI
24	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
25	Yoriko YK, Sei S, Naoki H and Kaori F: Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncol Rep. 30:1087–1093. 2013. View Article : Google Scholar : PubMed/NCBI
26	Stanley A, Ashrafi GH, Seddon AM and Modjtahedi H: Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines. Sci Rep. 7:39642017. View Article : Google Scholar : PubMed/NCBI
27	Sampera A, Sánchez-Martín FJ, Arpí O, Visa L, Iglesias M, Menéndez S, Gaye É, Dalmases A, Clavé S, Gelabert-Baldrich M, et al: HER-family ligands promote acquired resistance to trastuzumab in gastric cancer. Mol Cancer Ther. 18:2135–2145. 2019. View Article : Google Scholar : PubMed/NCBI
28	Derakhshani A, Rezaei Z, Safarpour H, Sabri M, Mir A, Sanati MA, Vahidian F, Gholamiyan Moghadam A, Aghadoukht A, Hajiasgharzadeh K and Baradaran B: Overcoming trastuzumab resistance in HER2-positive breast cancer using combination therapy. J Cell Physiol. 235:3142–3156. 2020. View Article : Google Scholar : PubMed/NCBI
29	Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA and Arteaga CL: Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 13:4909–4919. 2007. View Article : Google Scholar : PubMed/NCBI
30	Kumar R: ErbB-dependent signaling as a determinant of trastuzumab resistance. Clin Cancer Res. 13:4657–4659. 2007. View Article : Google Scholar : PubMed/NCBI
31	Shitara K, Hara H, Yoshikawa T, Fujitani K, Nishina T, Hosokawa A, Asakawa T, Kawakami S and Muro K: Pertuzumab plus trastuzumab and chemotherapy for Japanese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: A subgroup analysis of the JACOB trial. Int J Clin Oncol. 25:301–311. 2020. View Article : Google Scholar : PubMed/NCBI
32	Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K and Kang YK: Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 19:1372–1384. 2018. View Article : Google Scholar : PubMed/NCBI