Physical Sciences and Mathematics Commons^™

Sorafenib Resistance And Jnk Signaling In Carcinoma During Extracellular Matrix Stiffening, Thuy V. Nguyen, Marianne Sleiman, Timothy Moriarty, William G. Herrick, Shelly Peyton

Chemical Engineering Faculty Publication Series

Tumor progression is coincident with mechanochemical changes in the extracellular matrix (ECM). We hypothesized that tumor stroma stiffening, alongside a shift in the ECM composition from a basement membrane-like microenvironment toward a dense network of collagen-rich fibers during tumorigenesis, confers resistance to otherwise powerful chemotherapeutics. To test this hypothesis, we created a high-throughput drug screening platform based on our poly(ethylene glycol)-phosphorylcholine (PEG-PC) hydrogel system, and customized it to capture the stiffness and integrin-binding profile of in vivo tumors. We report that the efficacy of a Raf kinase inhibitor, sorafenib, is reduced on stiff, collagen-rich microenvironments, independent of ROCK activity. Instead, …