Research ArticleCancer

A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer

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Science Translational Medicine  23 Jan 2019:
Vol. 11, Issue 476, eaav1620
DOI: 10.1126/scitranslmed.aav1620

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A protein treatment for resistant cancer

The human epidermal growth factor receptor 2 (HER2) is present in many breast cancers and can be targeted using drugs such as trastuzumab. Unfortunately, tumors develop resistance to HER2 inhibitors, and additional options are needed to overcome it. Yang et al. discovered that a protein called peptidase D can target HER2 and the epidermal growth factor receptor (EGFR), which helps drive resistance. The authors designed an enzymatically inactive form of peptidase D, which blocks HER2 and EGFR but is otherwise inactive. They showed that it works by a different mechanism than preexisting drugs targeting these receptors and thus helps to overcome drug resistance.

Abstract

Resistance to current human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab (Ttzm), is a major unresolved clinical problem in HER2-positive breast cancer (HER2-BC). Because HER2 remains overexpressed in drug-resistant HER2-BC cells, we investigated whether PEPDG278D can overcome the resistance. PEPDG278D is a recombinant enzymatically inactive mutant of human peptidase D, which strongly inhibits HER2 in cancer cells by binding to its extracellular domain. Here, we show that PEPDG278D is highly active in preclinical models of HER2-BC resistant to Ttzm and other HER2 inhibitors and also enhances the therapeutic efficacy of paclitaxel. The therapeutic activity is underscored by its ability to bind to HER2 and free it from protection by mucin 4, disrupt its interplay with other receptor tyrosine kinases, and subsequently direct HER2 for degradation. PEPDG278D also down-regulates epidermal growth factor receptor, which contributes to drug resistance in HER2-BC. In contrast, Ttzm, whose therapeutic activity also depends on its binding to the extracellular domain of HER2, cannot perform any of these functions of PEPDG278D. PEPDG278D inhibits HER2-BC cells and tumors that carry clinically relevant molecular changes that confer resistance to Ttzm. Our results show that HER2 remains a critical target in drug-resistant HER2-BC and that PEPDG278D is a promising agent for overcoming drug resistance in this disease.

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