A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance

• DOI: 10.1039/c7ib00128b
• Publication Date: 2017-11-14T11:33:02Z
• Authors: Alyssa D. Schwartz; Lauren E. Barney; Lauren E. Jansen; Thuy V. Nguyen; Christopher L. Hall; Aaron S. Meyer; Shelly R. Peyton
• Keywords: Kinome

Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform depth, leaving gap understanding how extracellular signals such as stiffness, dimensionality, and cell–cell contacts act independently or are integrated within affect either sensitivity This is critically important, adaptive resistance mediated, at least part, by matrix (ECM) microenvironment. We developed an approach screen responses cells cultured on 2D 3D environments explore key ECM mediate response. uncovered hydrogels spheroids encapsulated were less responsive receptor tyrosine kinase (RTK)-targeting drugs sorafenib lapatinib, but not cytotoxic drugs, compared plastic. found transcriptomic differences between these vitro models xenografts did reveal mechanisms ECM-mediated sorafenib. However, systems biology analysis phospho-kinome data variation MEK phosphorylation was associated with RTK-targeted Using model drug, we co-administration inhibitor decreased reduced vivo burden alone. In sum, provide novel strategy for identifying overcoming performing screening, analysis, across multiple environments.