HER3 targeting with an antibody-drug conjugate bypasses resistance to anti-HER2 therapies

EMBO Mol Med. 2020 May 8;12(5):e11498. doi: 10.15252/emmm.201911498. Epub 2020 Apr 24.

Abstract

Despite impressive clinical benefit obtained with anti-HER2-targeted therapies, in advances stages, especially in the metastatic setting, HER2-positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody-drug conjugate EV20/MMAF exerted potent anti-tumoral properties against several models of primary resistance and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab-emtansine. HER3 was expressed in these HER2+ breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2+ cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2+ cancer clinic, including situations in which HER2+ tumors become refractory to approved anti-HER2 therapies.

Keywords: HER2; HER3; breast cancer; drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immunoconjugates* / pharmacology
  • Mice
  • Receptor, ErbB-2
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use

Substances

  • Antineoplastic Agents
  • Immunoconjugates
  • Receptor, ErbB-2
  • Trastuzumab