3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Mol Cancer Ther. 2016 Apr;15(4):753-63. doi: 10.1158/1535-7163.MCT-15-0598. Epub 2016 Feb 12.


There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • In Vitro Techniques
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / surgery
  • Neoplasm Staging
  • Phenotype
  • Standard of Care*
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism
  • Tissue Culture Techniques
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Biomarkers
  • Histone Deacetylase Inhibitors