Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma

Cui, Jinfang; He, Yuchao; Zhu, Fuyi; Gong, Wenchen; Zuo, Ran; Wang, Yu; Luo, Yi; Chen, Liwei; Wang, Chengmeng; Huo, Gengwei; Lu, Hailing; Liu, Zhiyong; Chen, Peng; Guo, Hua

doi:10.7150/ijbs.82980

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Int J Biol Sci 2023; 19(13):4061-4081. doi:10.7150/ijbs.82980 This issue Cite

Research Paper

Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma

Jinfang Cui^1,2,3†, Yuchao He^1,3†, Fuyi Zhu^1,2,3, Wenchen Gong^3,4, Ran Zuo^1,2,3, Yu Wang^1,2,3, Yi Luo^1,3, Liwei Chen^1,3, Chengmeng Wang^1,3, Gengwei Huo^2,3, Hailing Lu⁵, Zhiyong Liu^1,3✉, Peng Chen^2,3✉, Hua Guo^1,3✉

1. Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
2. Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
3. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
4. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
5. Department of Oncology, First Hospital of Harbin Medical University, Harbin, 150000, China.
†These authors contributed equally to this work.

✉ Corresponding authors: Hua Guo, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China, Tel.: +86 22 23537796, fax: +86 22 23537796, E-mail: guohuacom; Peng Chen, Tianjin Medical University Cancer Institute and Hosp More

Citation:

Cui J, He Y, Zhu F, Gong W, Zuo R, Wang Y, Luo Y, Chen L, Wang C, Huo G, Lu H, Liu Z, Chen P, Guo H. Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma. Int J Biol Sci 2023; 19(13):4061-4081. doi:10.7150/ijbs.82980. https://www.ijbs.com/v19p4061.htm

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Abstract

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms.

Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ.

Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

Keywords: anti-HER2 monoclonal antibody, lung adenocarcinoma, cisplatin, HER2/AKT/Nrf2 signaling pathway, pyroptosis

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APA

Cui, J., He, Y., Zhu, F., Gong, W., Zuo, R., Wang, Y., Luo, Y., Chen, L., Wang, C., Huo, G., Lu, H., Liu, Z., Chen, P., Guo, H. (2023). Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma. International Journal of Biological Sciences, 19(13), 4061-4081. https://doi.org/10.7150/ijbs.82980.

ACS

Cui, J.; He, Y.; Zhu, F.; Gong, W.; Zuo, R.; Wang, Y.; Luo, Y.; Chen, L.; Wang, C.; Huo, G.; Lu, H.; Liu, Z.; Chen, P.; Guo, H. Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma. Int. J. Biol. Sci. 2023, 19 (13), 4061-4081. DOI: 10.7150/ijbs.82980.

NLM

CSE

Cui J, He Y, Zhu F, Gong W, Zuo R, Wang Y, Luo Y, Chen L, Wang C, Huo G, Lu H, Liu Z, Chen P, Guo H. 2023. Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma. Int J Biol Sci. 19(13):4061-4081.

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