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

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.