Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kwanghee Kim, Wenhuo Hu, François Audenet, Nima Almassi, Aphrothiti J. Hanrahan, Katie Murray, Aditya Bagrodia, Nathan Wong, Timothy N. Clinton, Shawn Dason, Vishnu Mohan, Sylvia Jebiwott, Karan Nagar, Jianjiong Gao, Alex Penson, Chris Hughes, Benjamin Gordon, Ziyu Chen, Yiyu Dong, Philip A. WatsonRicardo Alvim, Arijh Elzein, Sizhi P. Gao, Emiliano Cocco, Alessandro D. Santin, Irina Ostrovnaya, James J. Hsieh, Irit Sagi, Eugene J. Pietzak, A. Ari Hakimi, Jonathan E. Rosenberg, Gopa Iyer, Herbert A. Vargas, Maurizio Scaltriti, Hikmat Al-Ahmadie, David B. Solit, Jonathan A. Coleman

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

Original languageEnglish (US)
Article number1975
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Kim, K., Hu, W., Audenet, F., Almassi, N., Hanrahan, A. J., Murray, K., Bagrodia, A., Wong, N., Clinton, T. N., Dason, S., Mohan, V., Jebiwott, S., Nagar, K., Gao, J., Penson, A., Hughes, C., Gordon, B., Chen, Z., Dong, Y., ... Coleman, J. A. (2020). Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts. Nature communications, 11(1), [1975]. https://doi.org/10.1038/s41467-020-15885-7