TY - JOUR
T1 - ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer
AU - VanSchaeybroeck, Sandra
AU - Kalimutho, Murugan
AU - Dunne, Philip D.
AU - Carson, Robbie
AU - Allen, Wendy
AU - Jithesh, Puthen V.
AU - Redmond, Keara L.
AU - Sasazuki, Takehiko
AU - Shirasawa, Senji
AU - Blayney, Jaine
AU - Michieli, Paolo
AU - Fenning, Cathy
AU - Lenz, Heinz Josef
AU - Lawler, Mark
AU - Longley, Daniel B.
AU - Johnston, Patrick G.
N1 - Funding Information:
This study was supported by Cancer Research UK (C212/A7402) and a Cancer Research UK fellowship (C13749/A13172). P.G.J. is employed by ALMAC Diagnostics and has ownership interest in both ALMAC Diagnostics and Fusion Antibodies. He is a consultant/advisor for, and has received honoraria from, Chugai Pharmaceuticals, Sanofi-Aventis, and Pfizer.
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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 toMEK inhibitors in KRASMT CRC invitro and invivo.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 tobe 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 synergisticallyincreased MEK-inhibitor-induced apoptosis and growth inhibition invitro and invivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.
AB - 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 toMEK inhibitors in KRASMT CRC invitro and invivo.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 tobe 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 synergisticallyincreased MEK-inhibitor-induced apoptosis and growth inhibition invitro and invivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.
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U2 - 10.1016/j.celrep.2014.05.032
DO - 10.1016/j.celrep.2014.05.032
M3 - Article
C2 - 24931611
AN - SCOPUS:84903441759
SN - 2211-1247
VL - 7
SP - 1940
EP - 1955
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -
