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

Sandra VanSchaeybroeck, 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

Research output: Contribution to journalArticle

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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 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.

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

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

VanSchaeybroeck, S., Kalimutho, M., Dunne, P. D., Carson, R., Allen, W., Jithesh, P. V., ... Johnston, P. G. (2014). ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer. Cell Reports, 7(6), 1940-1955. https://doi.org/10.1016/j.celrep.2014.05.032

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

VanSchaeybroeck, S, Kalimutho, M, Dunne, PD, Carson, R, Allen, W, Jithesh, PV, Redmond, KL, Sasazuki, T, Shirasawa, S, Blayney, J, Michieli, P, Fenning, C, Lenz, HJ, Lawler, M, Longley, DB & Johnston, PG 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. https://doi.org/10.1016/j.celrep.2014.05.032
VanSchaeybroeck, 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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AU - Carson, Robbie

AU - Allen, Wendy

AU - Jithesh, Puthen V.

AU - Redmond, Keara L.

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AU - Blayney, Jaine

AU - Michieli, Paolo

AU - Fenning, Cathy

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AU - Lawler, Mark

AU - Longley, Daniel B.

AU - Johnston, Patrick G.

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