Article | Published:

An HER3-targeting antibody–drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC

Oncogene (2018) | Download Citation

Abstract

EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody–drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.

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Acknowledgements

We thank Haruka Yamaguchi, Yume Shinkai, and Michiko Kitano for technical support.

Author information

Affiliations

  1. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan

    • Kimio Yonesaka
    • , Naoki Takegawa
    • , Satomi Watanabe
    • , Koji Haratani
    • , Hisato Kawakami
    •  & Kazuhiko Nakagawa
  2. Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan

    • Kazuko Sakai
    •  & Kazuto Nishio
  3. Clinical Research Center, Kindai University Hospital, Osaka-Sayamashi, Osaka, Japan

    • Yasutaka Chiba
  4. Biomarker Department, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan

    • Naoyuki Maeda
  5. Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan

    • Takashi Kagari
  6. Oncology Clinical Development Department, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan

    • Kenji Hirotani

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Conflict of interest

Dr. Yonesaka and Dr. Nakagawa received research funding from Daiichi Sankyo Co., Ltd., and Dr. Maeda, Dr. Kagari, and Dr. Hirotani are employees of Daiichi Sankyo Co., Ltd. The remaining authors declare that they have no conflict of interest.

Financial support

This study was financially supported by Daiichi Sankyo Co., Ltd. U3-1402 and patritumab were provided by Daiichi Sankyo Co., Ltd.

Corresponding author

Correspondence to Kimio Yonesaka.

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DOI

https://doi.org/10.1038/s41388-018-0517-4