2. Academic Validation
  3. Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism

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

  • Br J Cancer. 2024 Jul 10. doi: 10.1038/s41416-024-02788-3.
Che-Yuan Hsu 1 2,  Teruki Yanagi 3 4,  Takuya Maeda 1,  Hiroshi Nishihara 5,  Takeru Funakoshi 6,  Kodai Miyamoto 1 2,  Ririko Iwamoto 2,  Kenzo Takahashi 2,  Hideyuki Ujiie 1
Affiliations

Affiliations

  • 1 Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • 2 Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
  • 3 Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. yanagi@med.hokudai.ac.jp.
  • 4 Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. yanagi@med.hokudai.ac.jp.
  • 5 Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
  • 6 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
PMID: 38987365 DOI: 10.1038/s41416-024-02788-3
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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