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A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

Abstract

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

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Publication details

The article was received on 24 Jul 2017, accepted on 13 Nov 2017 and first published on 14 Nov 2017


Article type: Paper
DOI: 10.1039/C7IB00128B
Citation: Integr. Biol., 2017, Accepted Manuscript
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    A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance

    A. D. Schwartz, L. E. Barney, L. E. Jansen, T. V. Nguyen, C. L. Hall, A. A. Meyer and S. Peyton, Integr. Biol., 2017, Accepted Manuscript , DOI: 10.1039/C7IB00128B

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