Patient-derived xenografts and organoids model therapy response in prostate cancer. Academic Article uri icon

Overview

abstract

  • Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

publication date

  • February 18, 2021

Research

keywords

  • Models, Biological
  • Organoids
  • Prostatic Neoplasms
  • Xenograft Model Antitumor Assays

Identity

PubMed Central ID

  • PMC7892572

Scopus Document Identifier

  • 85101267004

Digital Object Identifier (DOI)

  • 10.1038/s42003-019-0305-x

PubMed ID

  • 33602919

Additional Document Info

volume

  • 12

issue

  • 1