Sustained activation of the AKT/mTOR and MAP kinase pathways mediate resistance to the Src inhibitor, dasatinib, in thyroid cancer
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Katie M. Mishall1, Thomas C. Beadnell1, Brent M. Kuenzi2,3, Dorothy M. Klimczak1, Giulio Superti-Furga4,5, Uwe Rix2 and Rebecca E. Schweppe1
1Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
2Department of Drug Discovery, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
3Cancer Biology PhD Program, University of South Florida, Tampa, Florida, USA
4CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
5Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Rebecca E. Schweppe, email: [email protected]
Keywords: Src, thyroid cancer, dasatinib, bosutinib, compound centric proteomics
Abbreviations: DasRes: dasatinib-resistant; CCCP: compound centric chemical proteomics; BSKs: bosutinib specific kinases; MAPK: mitogen activated protein kinase
Received: May 24, 2017 Accepted: July 23, 2017 Published: August 24, 2017
New targeted therapies are needed for advanced thyroid cancer. Our lab has shown that Src is a key mediator of tumorigenic processes in thyroid cancer. However, single-agent Src inhibitors have had limited efficacy in solid tumors. In order to more effectively target Src in the clinic, our lab has previously generated four thyroid cancer cell lines that are resistant to dasatinib through gradual dose escalation. We further tested two additional Src inhibitors and shown the dasatinib-resistant (DasRes) cells exhibit cross-resistance to saracatinib, but are sensitive to bosutinib, suggesting that unique off-targets of bosutinib play an important role in mediating sensitivity to bosutinib. To identify the kinases targeted by dasatinib and bosutinib, we utilized an unbiased compound centric chemical proteomics screen. We identified 33 kinases that were enriched in the bosutinib pull down. Using the STRING database to map protein-protein interactions of the unique bosutinib targets, we identified a signaling axis which included mTOR, FAK, and MEK. Inhibition of the mTOR, MEK, and Src/FAK nodes simultaneously was the most effective at reducing cell growth and survival. Overall, these studies have identified key mediators of Src inhibitor resistance, and show that targeting these signaling nodes are necessary for anti-tumor efficacy.
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