Systematic Evaluation of Gastric Tumor Cell Index and Two-Drug Combination Therapy via 3-Dimensional High-Throughput Drug Screening

Sung Hee Lim, Jason K. Sa, Dong Woo Lee, Jusun Kim, Seung Tae Kim, Se Hoon Park, Bosung Ku, Joon Oh Park, Young Suk Park, Hoyeong Lim, Won Ki Kang, Do Hyun Nam, Jeeyun Lee

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Tumor heterogeneity greatly limits personalized treatment of cancer. Patient-derived tumor cell (PDC) models precisely recapitulate the molecular properties and biology of the disease, making them effective preclinical tools for assessing anti-cancer drug activities. Accurate estimation of tumor purity is essential for performing high-throughput drug screening (HTS). In the present study, we measured and predicted the tumor population index in PDC models for two-drug combinational strategies using HTS system. Gastric cancer cell-lines and PDCs were subjected to multi-color immunofluorescence analysis against EpCAM and vimentin to evaluate the tumor cell index based on EpCAM expression levels. We generated a tumor purity prediction model using five different gastric cancer cell-lines (AGS, KATO-III, MKN-45, NCI-N87, SNU-216) with fluorescence intensity-based techniques. Afterwards, stage IV gastric cancer PDC models were evaluated using a micropillar/microwell chip-based HTS system. HER2/CCNE1-amplified PDCs were considerably resistant to an HER2 inhibitor, while combinational treatment consisting of an HER2 inhibitor with anti-WEE1 compound substantially suppressed tumor cellular growth. Moreover, PDCs with BRCA1/2 mutations were synergistically sensitive to HER2 and PARP inhibition therapy. Finally, somatic mutations in TP53 and CDKN2A with MYC amplification rendered PDCs susceptible to the drug combination of WEE1 and HER2. Collectively, our systematic method of high-throughput drug sensitivity screening is an integral pre-clinical platform for evaluating potential two-drug combinational approaches for personalized treatment of cancer.

Original languageEnglish
Article number1327
JournalFrontiers in Oncology
Volume9
DOIs
Publication statusPublished - 2019 Nov 29

Keywords

  • high-throughput drug screening
  • patient-derived tumor cell
  • tumor heterogeneity
  • tumor purity
  • two-drug combination

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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