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Updated: Feb 18, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance
Alyssa D Schwartz1, Lauren E Barney, Lauren E Jansen
1Department of Chemical Engineering, University of Massachusetts Amherst, 686 N Pleasant St. 159 Goessmann Laboratory, Amherst, MA 01003, USA. speyton@ecs.umass.edu.
Abstract:
Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity 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 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. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in 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.
Insights
Tumor microenvironment features like extracellular matrix (ECM) drive drug resistance. Combining drug screening with systems biology in 2D and 3D models identified MEK phosphorylation as a key resistance mechanism, suggesting MEK inhibitors can overcome this.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Pharmacology
Background:
- Traditional drug screening omits tumor microenvironment (TME) factors crucial for drug resistance.
- Extracellular matrix (ECM) properties like stiffness and dimensionality significantly influence cancer cell drug sensitivity.
- A gap exists in understanding how TME signals are integrated to affect drug response.
Purpose of the Study:
- To develop and utilize a multi-platform screening approach (2D and 3D biomaterials) to investigate ECM-mediated drug resistance.
- To identify molecular mechanisms underlying ECM-driven resistance to receptor tyrosine kinase (RTK)-targeting drugs.
- To explore strategies for overcoming ECM-mediated drug resistance.
Main Methods:
- Cultured cells on 2D hydrogels and within 3D hydrogel microenvironments (spheroids).
- Screened responses to RTK-targeting drugs (sorafenib, lapatinib) and cytotoxic drugs across different biomaterial platforms.
- Conducted transcriptomic and phospho-kinome analyses, integrating with systems biology approaches.
- Performed in vitro and in vivo validation using MEK inhibitors in combination with sorafenib.
Main Results:
- Cells in 2D and 3D biomaterial environments showed reduced sensitivity to RTK-targeting drugs compared to single cells or cells on plastic.
- Transcriptomic analysis did not fully explain ECM-mediated resistance to sorafenib.
- Phospho-kinome analysis revealed MEK phosphorylation variation correlated with RTK-targeted drug resistance.
- Co-administration of sorafenib with a MEK inhibitor reduced ECM-mediated resistance in vitro and tumor burden in vivo.
Conclusions:
- A novel multi-platform strategy effectively screens drug responses within diverse biomaterial environments.
- ECM significantly contributes to resistance against RTK-targeting drugs, mediated in part by MEK signaling.
- Targeting MEK in combination with RTK inhibitors offers a promising strategy to overcome ECM-mediated drug resistance.
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