ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in <i>KRAS</i> Mutant Colorectal Cancer
Data(s) |
26/06/2014
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Resumo |
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. |
Formato |
application/pdf |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/openAccess |
Fonte |
Van Schaeybroeck , S , Kalimutho , M , Dunne , P D , Carson , R , Allen , W , Jithesh , P V , Redmond , K L , Sasazuki , T , Shirasawa , S , Blayney , J , Michieli , P , Fenning , C , Lenz , H-J , Lawler , M , Longley , D B & Johnston , P G 2014 , ' ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer ' Cell Reports , vol 7 , no. 6 , pp. 1940-1955 . DOI: 10.1016/j.celrep.2014.05.032 |
Tipo |
article |