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Translational Therapeutics

Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism

British Journal of Cancer (2024)Cite this article

Subjects

Abstract

Background/objectives

Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab’s effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy.

Methods/subjects

In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours.

Results

Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan).

Conclusions

This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

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Fig. 1: Schematic illustration of the establishment of the trastuzumab-resistant EMPD-PDX mouse model and the treatment experiment.
Fig. 2: Comparison between trastuzumab-sensitive (TS) and several trastuzumab-resistant (TR) EMPD tumours based on the next-generation sequencing-based multiplex gene assay (PleSSision-160).
Fig. 3: Histology and immunoblot analysis of trastuzumab-sensitive (TS) and several trastuzumab-resistant (TR) EMPD-PDX tumours.
Fig. 4: Trastuzumab-resistant (TR) EMPD-PDX tumours show loss of PTEN, increased Akt phosphorylation and p27 downregulation.
Fig. 5: HER2-targeted therapies, cyclin‐dependent kinase 4/6 inhibitors and cytotoxic agents suppress tumour growth in the trastuzumab-resistant EMPD-PDX mouse model.
Fig. 6: Schematic illustration of the pathogenic mechanisms involved in trastuzumab-resistant EMPD-PDX.

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Data availability

Derived data supporting the findings of this study are available from the corresponding author (TY) on request.

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Acknowledgements

This work was supported by Hokkaido University DX Doctoral Fellowship (to C-YH).

Funding

This work was supported by JSPS KAKENHI Grant Number JP22K0839702 (to TY), Takagi Research Grant (to TY), Nakatomi Foundation grant (to TY), and the project of junior scientist promotion in Hokkaido University (to HU).

Author information

Authors and Affiliations

  1. Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Che-Yuan Hsu, Teruki Yanagi, Takuya Maeda, Kodai Miyamoto & Hideyuki Ujiie

  2. Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

    Che-Yuan Hsu, Teruki Yanagi, Kodai Miyamoto, Ririko Iwamoto & Kenzo Takahashi

  3. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Hiroshi Nishihara

  4. Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

    Takeru Funakoshi

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  1. Che-Yuan Hsu
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Contributions

Conceptualisation: TY. Methodology: C-YH, TY, HN and TF. Validation: TM, KM and RI. Formal analysis: HU. Investigation: C-YH, TM and TY. Resources: TY, KT and HU. Data curation: TM and KT. Writing—original draft preparation: C-YH. Writing—review and editing: TY and HU. Visualisation: TM. Supervision: HU. Project administration: TY and HU. Funding acquisition: TY.

Corresponding author

Correspondence to Teruki Yanagi.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study protocol complied with the Declaration of Helsinki and was approved by the Institutional Review Board of Keio University (IRB approval number: 20110159). The 73-year-old Japanese male EMPD patient provided written informed consent prior to enrollment. The animal study protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Hokkaido University (approval number 19-0093) and the Committee on Animal Experiments of the University of the Ryukyus (approval number A2023052), and all experiments were performed in accordance with the regulations of IACUC. All methods are reported in accordance with ARRIVE guidelines (https://arriveguidelines.org) for the reporting of animal experiments under ethics approval and consent to participate.

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Hsu, CY., Yanagi, T., Maeda, T. et al. Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02788-3

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