3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors

Onion, David; Argent, Richard H.; Reece-Smith, Alex M.; Craze, Madeleine L.; Pineda, Robert G.; Clarke, Philip A.; Ratan, Hari L.; Parsons, Simon L.; Lobo, Dileep N.; Duffy, John P.; Atherton, John C.; McKenzie, Andrew J.; Kumari, Rajendra; King, Peter; Hall, Brett M.; Grabowska, Anna M.

Abstract

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.

Citation

Onion, D., Argent, R. H., Reece-Smith, A. M., Craze, M. L., Pineda, R. G., Clarke, P. A., Ratan, H. L., Parsons, S. L., Lobo, D. N., Duffy, J. P., Atherton, J. C., McKenzie, A. J., Kumari, R., King, P., Hall, B. M., & Grabowska, A. M. (2016). 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors. Molecular Cancer Therapeutics, 15(4), https://doi.org/10.1158/1535-7163.MCT-15-0598

• Journal Article Type: Article
• Acceptance Date: Jan 6, 2016
• Publication Date: Apr 1, 2016
• Deposit Date: Feb 9, 2017
• Publicly Available Date: Feb 9, 2017
• Journal: Molecular Cancer Therapeutics
• Print ISSN: 1535-7163
• Electronic ISSN: 1538-8514
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 4
• DOI: https://doi.org/10.1158/1535-7163.MCT-15-0598
• Public URL: https://nottingham-repository.worktribe.com/output/777976
• Publisher URL: http://dx.doi.org/10.1158/1535-7163.MCT-15-0598
• Contract Date: Feb 9, 2017