Utilizing patient-derived epithelial ovarian cancer tumor organoids to predict carboplatin resistance

Justin W. Gorski, Zhuwei Zhang, J. Robert Mccorkle, Jodi M. Dejohn, Chi Wang, Rachel W. Miller, Holly H. Gallion, Charles S. Dietrich, Frederick R. Ueland, Jill M. Kolesar

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

Original languageEnglish
Article number1021
JournalBiomedicines
Volume9
Issue number8
DOIs
StatePublished - Aug 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Carboplatin
  • Chemotherapy resistance
  • Integrated genetic analysis
  • Ovarian cancer
  • Tumor organoids

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology

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