Acquired resistance to trastuzumab/pertuzumab or to T-DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728.

Abstract

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.

• Authors: Hiroki Irie, Rumi Kawabata, Yayoi Fujioka, Fumio Nakagawa, Hiraku Itadani, Hideki Nagase, Kimihiro Ito, Junji Uchida, Shuichi Ohkubo, Kenichi Matsuo
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 6 Pg. 2123-2131 (Jun 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32248641 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Protein Kinase Inhibitors
• ERBB2 protein, human
• ERBB3 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3
• pertuzumab
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine (pharmacology)
• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Mice
• Mice, Nude
• Protein Kinase Inhibitors (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Receptor, ErbB-3 (metabolism)
• Signal Transduction (drug effects)
• Trastuzumab (pharmacology)
• Xenograft Model Antitumor Assays