npj Breast Cancer (Apr 2022)

Therapeutic and immunomodulatory potential of pazopanib in malignant phyllodes tumor

  • Dave Yong Xiang Ng,
  • Zhimei Li,
  • Elizabeth Lee,
  • Jessica Sook Ting Kok,
  • Jing Yi Lee,
  • Joanna Koh,
  • Cedric Chuan-Young Ng,
  • Abner Herbert Lim,
  • Wei Liu,
  • Sheng Rong Ng,
  • Kah Suan Lim,
  • Xi Xiao Huang,
  • Jing Han Hong,
  • Peiyong Guan,
  • Yirong Sim,
  • Aye Aye Thike,
  • Nur Diyana Md Nasir,
  • Shang Li,
  • Puay Hoon Tan,
  • Bin Tean Teh,
  • Jason Yongsheng Chan

DOI
https://doi.org/10.1038/s41523-022-00413-1
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 10

Abstract

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Abstract Malignant phyllodes tumors (PT) are rare aggressive fibroepithelial neoplasms with high metastatic potential and lack effective therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MPT-S1) of malignant PT which demonstrated clinical response to pazopanib. Whole exome sequencing identified somatic mutations in TP53, RB1, MED12, and KMT2D. Immunohistochemistry and genomic profiles of the tumor, PDX and cell line were concordant. In keeping with clinical observation, pazopanib reduced cell viability in a dose-dependent manner and evoked apoptosis, and led to significant abrogation of in vivo tumor growth. Whole transcriptomic analysis revealed that pazopanib decreased expression of genes involved in oncogenic and apoptosis signaling. We also observed decreased expression of ENPP1, with known roles in cancer invasion and metastasis, as well as STING pathway upregulation. Accordingly, pazopanib induced micronuclei formation, and evoked phospho-TBK1 and PD-L1 expression. In an additional cohort of malignant PT (n = 14), six (42.9%) showed comparable or higher levels of ENPP1 relative to MPT-S1, highlighting its potential role as a therapeutic target. In conclusion, we established MPT-S1, a new PDX and cell line model, and provided evidence for the clinical efficacy of pazopanib in malignant PT.