Development of an ALK-positive Non-Small-Cell Lung Cancer in Vitro Tumor 3D Culture Model for Therapeutic Screening.

Abstract

Cancer cell monolayers are commonly used for preclinical drug screening. However, monolayers do not begin to mimic the complexity of the tumor microenvironment, including hypoxia and nutrient gradients within the tumor. To more accurately mimic solid tumors, we developed and drug-tested an anaplastic lymphoma kinase (ALK)-positive (H3122) non-small-cell lung cancer 3D (three-dimensional) culture model using light-activated gelatin methacryloyl hydrogels. We previously demonstrated that the combination of alectinib, an ALK inhibitor, and SHP099, an SHP2 inhibitor, had synergistic efficacy in ALK-positive cell monolayers. We aimed to test this drug combination in our novel ALK-positive 3D cancer model. We first validated the 3D cultures by comparing the distribution of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the 3D cultures with sections from time-matched mouse xenografts, finding a comparable percentage of TUNEL-positive cells in the 3D culture and xenograft inner cores at each time point. When we investigated the effect of the combination of alectinib and SHP099 in these novel 3D cultures, we found a comparable cellular response compared with our two-dimensional experiments especially with the drugs in combination. We suggest that 3D cultures be used as preclinical screening platforms to ensure that only the most efficacious drug candidates move on to in vivo testing.