ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer

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, Patrick G. Johnston

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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.
Original languageEnglish
Pages (from-to)1940-1955
Number of pages16
JournalCell Reports
Volume7
Issue number6
Early online date12 Jun 2014
DOIs
Publication statusPublished - 26 Jun 2014

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Mitogen-Activated Protein Kinase Kinases
Colorectal Neoplasms
Chemical activation
Systems Biology
Metalloproteases
Pharmacology
Apoptosis
ADAM17 Protein
Therapeutics
Growth
In Vitro Techniques

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Van Schaeybroeck, Sandra ; Kalimutho, Murugan ; Dunne, Philip D. ; Carson, Robbie ; Allen, Wendy ; Jithesh, Puthen V. ; Redmond, Keara L. ; Sasazuki, Takehiko ; Shirasawa, Senji ; Blayney, Jaine ; Michieli, Paolo ; Fenning, Cathy ; Lenz, Heinz-Josef ; Lawler, Mark ; Longley, Daniel B. ; Johnston, Patrick G. / ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer. In: Cell Reports. 2014 ; Vol. 7, No. 6. pp. 1940-1955.
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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.",
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ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer. / Van Schaeybroeck, Sandra; Kalimutho, Murugan; Dunne, Philip D.; Carson, Robbie; Allen, Wendy; Jithesh, Puthen V.; Redmond, Keara L.; Sasazuki, Takehiko; Shirasawa, Senji; Blayney, Jaine; Michieli, Paolo; Fenning, Cathy; Lenz, Heinz-Josef; Lawler, Mark; Longley, Daniel B.; Johnston, Patrick G.

In: Cell Reports, Vol. 7, No. 6, 26.06.2014, p. 1940-1955.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer

AU - Van Schaeybroeck, 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.

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 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.

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 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.

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DO - 10.1016/j.celrep.2014.05.032

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