Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Oncotarget
Chao WangBohua Li

Abstract

Trastuzumab resistance is a common problem that impedes the effectiveness of trastuzumab in ErbB2-amplified cancers. About 70% of ErbB2-amplified breast cancers do not respond to trastuzumab (de novo resistance), and the majority of the trastuzumab-responsive cancers progress within 1 year (acquired resistance). Different mechanisms exist between de novo and acquired resistance. Innate resistance mechanisms are mainly independent of ErbB2 receptor activity, and acquired resistance involves with alterations depending on ErbB2 activity. We previously reported H2-18, an ErbB2 domain I-specific antibody, which could circumvent de novo resistance to trastuzumab. Here, we modeled the development of acquired resistance by treating human gastric cancer cell line NCI-N87 with trastuzumab to obtain the trastuzumab-resistant subline, NCI-N87-TraRT. Next, we investigated the antitumor efficacy of H2-18 in NCI-N87-TraRT cell line. H2-18 exhibited a significantly greater antitumor activity in NCI-N87-TraRT tumor-bearing nude mice than pertuzumab and trastuzumab, either alone or in combination. The unique ability of H2-18 to overcome acquired resistance may be attributable to its potent programmed cell death-inducing activity, which was proba...Continue Reading

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Citations

Aug 15, 2020·Frontiers in Oncology·Sudath Hapuarachchige, Dmitri Artemov
Jul 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Rosalynd UptonIrving L Weissman

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Methods Mentioned

BETA
xenografts
flow cytometry
gene knockdown
transfection

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