Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism
Journal
British Journal of Cancer
Journal Volume
131
Journal Issue
5
Start Page
944-953
ISSN
0007-0920
1532-1827
Date Issued
2024-07-10
Author(s)
Yanagi, Teruki
Maeda, Takuya
Nishihara, Hiroshi
Funakoshi, Takeru
Miyamoto, Kodai
Iwamoto, Ririko
Takahashi, Kenzo
Ujiie, Hideyuki
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.
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article