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.

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

Capone E.;Sala G.
;
2020

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11564/720272
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