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Extramammary Paget’s disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies

Oncogene volume 39, pages 5867–5875 (2020)Cite this article

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Abstract

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.

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Fig. 1: Schematic of the study method.
Fig. 2: The clinical manifestations and immunohistopathological findings for the primary site, the metastatic lymph node, and EMPD-PDX-H1.
Fig. 3: EMPD-PDX-H1 tumors harbor ERBB2 gene mutations identical to those of the patient’s primary and metastatic tumors.
Fig. 4: HER2-targeted therapies suppress the tumor growth of EMPD-PDX-H1 harboring the ERBB2 S310F mutation.
Fig. 5: EMPD-PDX-H1 are sensitive to cytotoxic agents, including eribulin and docetaxel.

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Acknowledgements

We thank Ms. Yuko Tateda for her technical assistance. This work was supported in part by KAKENHI grant #18K08259 to TY from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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  1. These authors contributed equally: Takuya Maeda, Shinya Kitamura

Authors and Affiliations

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

    Takuya Maeda, Shinya Kitamura & Teruki Yanagi

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

    Hiroshi Nishihara

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Correspondence to Teruki Yanagi.

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Maeda, T., Kitamura, S., Nishihara, H. et al. Extramammary Paget’s disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies. Oncogene 39, 5867–5875 (2020). https://doi.org/10.1038/s41388-020-01404-x

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