1. ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer
- Author
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Sandra Van Schaeybroeck, Murugan Kalimutho, Philip D. Dunne, Robbie Carson, Wendy Allen, Puthen V. Jithesh, Keara L. Redmond, Takehiko Sasazuki, Senji Shirasawa, Jaine Blayney, Paolo Michieli, Cathy Fenning, Heinz-Josef Lenz, Mark Lawler, Daniel B. Longley, and Patrick G. Johnston
- Subjects
Biology (General) ,QH301-705.5 - Abstract
There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance to MEK inhibitors in KRASMT CRC in vitro and in vivo. Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found to be due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble “decoy” MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergistically increased MEK-inhibitor-induced apoptosis and growth inhibition in vitro and in vivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.
- Published
- 2014
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