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

There is a growing recognition that current pre-clinical 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 co-culture with patient-derived cancer-associated fibroblasts (CAFs). A range of solid tumors proved amenable to growth and pharmacological 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 standards-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.

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