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Cancer Lett. 2020 Mar 31;473:156-163. doi: 10.1016/j.canlet.2019.12.037. Epub 2020 Jan 2.

ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer.

Author information

1
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland; Laboratory of Molecular Oncology, University of Helsinki, Helsinki, FIN-00290, Finland. Electronic address: mark.barok@helsinki.fi.
2
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland. Electronic address: vadim.lejoncour@helsinki.fi.
3
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland. Electronic address: ana.martins@helsinki.fi.
4
Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland. Electronic address: jorma.isola@tuni.fi.
5
Laboratory of Molecular Oncology, University of Helsinki, Helsinki, FIN-00290, Finland. Electronic address: marko.salmikangas@helsinki.fi.
6
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland; Laboratory Animal Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland. Electronic address: pirjo.laakkonen@helsinki.fi.
7
Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland; Laboratory of Molecular Oncology, University of Helsinki, Helsinki, FIN-00290, Finland; Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, FIN-00029, Finland. Electronic address: heikki.joensuu@hus.fi.

Abstract

The majority of HER2-positive breast or gastric cancers treated with T-DM1 eventually show resistance to this agent. We compared the effects of T-DM1 and ARX788, a novel anti-HER2 antibody-drug conjugate, on cell growth and apoptosis in HER2-positive breast cancer and gastric cancer cell lines sensitive to T-DM1, gastric cancer cell lines resistant to T-DM1, HER2-negative breast cancer cell lines, and T-DM1-resistant xenograft models. ARX788 was effective in T-DM1-resistant in vitro and in vivo models of HER2-positive breast cancer and gastric cancer. ARX788 showed a pronounced growth inhibitory effect on all five HER2-positive cell lines tested, of which two gastric cancer cell lines had acquired resistance to T-DM1. ARX788 evoked more apoptotic events compared to T-DM1. While JIMT-1 and RN-87 xenograft tumors progressed on T-DM1 treatment, all such tumors responded to ARX788, and four out of the six JIMT-1 tumors and nine out of the twelve RN-87 tumors disappeared during the ARX788 treatment. Mice treated with ARX788 survived longer than those treated with T-DM1. The data support evaluation of ARX788 in patients with HER2-positive breast cancer or gastric cancer including cancers that progress during T-DM1 therapy.

KEYWORDS:

Apoptosis; Drug resistance; Human epidermal growth factor receptor 2; T-DM1; Xenograft

Conflict of interest statement

Declaration of competing interest Heikki Joensuu is a board member of Sartar Therapeutics, has a co-appointment at Orion Pharma, and has received fees from Orion Pharma and Neutron Therapeutics Ltd.

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