An intestinal matrix-based human lung cancer model reflects clinical data from gefitinib on dosage-dependent efficacy

Lung cancer is the leading cause for cancer related death worldwide. One treatment option for patients with pulmonary adenocarcinoma is the targeted therapy gefitinib (Iressa®, ZD1839). As with other promising targeted therapies, desired in vivo effects of gefitinib came short to in vitro expectations, as preclinical testing is hampered by an inaccuracy of existing models and resistances develop frequently. We analysed the pharmacodynamics of gefitinib in a 3D tissue engineered human lung cancer model of HCC827 cells, as well as a resistant subpopulation of HCCres A2 cells. In 2D cell culture, a cell viability of 50 % was reached after treatment with 0.01-0.05 μM gefitinib. In the 3D model administering higher doses of gefitinib did not lead to a further reduction in viability and proliferation, or an increase in apoptosis. This shows that the pharmacodynamic effect of promising new therapies can often be overestimated in 2D versus 3D models. The results we obtained for gefitinib testing in the 3D models reflect astonishing well the efficacy of priorly published clinical data, suggesting that our 3D tumor models can display in vivo conditions more accurately, bridging the gap to living organisms. To mimic the clinical setting further, the lung cancer cells were cultivated under dynamic conditions in a bioreactor. The exploration of a resistant subpopulation confirmed an epithelial-mesenchymal transition. The described 3D lung cancer model can be used as a refined, preclinical testing platform for targeted therapies and with clinically relevant pharmacodynamic properties as shown exemplary for gefitinib.