Extramammary Paget's disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies.
Aged
Amino Acid Substitution
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Cell Line, Tumor
DNA Mutational Analysis
Disease Models, Animal
Female
Humans
Mice
Molecular Targeted Therapy
Mutation
Paget Disease, Extramammary
/ drug therapy
Receptor, ErbB-2
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
15
05
2020
accepted:
20
07
2020
revised:
09
07
2020
pubmed:
30
7
2020
medline:
26
11
2020
entrez:
30
7
2020
Statut:
ppublish
Résumé
Although the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.
Identifiants
pubmed: 32724160
doi: 10.1038/s41388-020-01404-x
pii: 10.1038/s41388-020-01404-x
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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