The c-MET-JAK1/2-STAT3 signalling axis is regulated by ADAM17 and is a key mediator of resistance to MEK inhibition in KRAS mutant colorectal cancer

Sandra Van Schaeybroeck, Murugan Kalimutho, Philip Dunne, Wendy Moore, Puthen Jithesh, Catherine Fenning, Robbie Carson, Daniel Longley, Patrick Johnston

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Background
Mutations in the KRAS proto-oncogene are found in 40%-45% of colorectal cancer (CRC) patients and confer resistance to EGFR monoclonal antibody therapies. The identification of druggable targets that uniquely target KRAS mutant (MT) tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC.

Method
To identify novel targets/pathways which are critical for the survival of KRASMT tumours, both basally and following MEK1/2 treatment, we combined microarray data from isogenic in vivo KRAS wild type (WT) and MT CRC models, KRASWT/MT primary tumours, and publicly available datasets.

Results
Pathway analysis of the microarray data followed by siRNA screening revealed that JAK1/2-STAT3 signaling is an important pro-survival signal in KRASMT CRC cells. Moreover, suppression of JAK1/2-STAT3 activity using small molecule inhibitors resulted in apoptosis induction in KRASMT CRC cells. In addition, treatment with MEK inhibitors significantly increased JAK2-STAT3 activity in KRASMT but not wild-type models in vitro and in vivo. c-MET was identified as the upstream receptor that promotes JAK1/2-STAT3-mediated resistance to MEK inhibitors in KRASMT CRC cells. Importantly, ADAM17 was found to mediate this feedback activation of c-MET. Furthermore, combinations of either c-MET or JAK1/2 inhibitors with MEK inhibitors led to marked increases in apoptosis and dramatically attenuated tumor growth in vivo. These findings support the clinical assessment of combined JAK1/2-MEK or c-MET-MEK inhibition for the treatment of KRASMT CRC.

Conclusion
Using a systems biology approach, we have identified an essential role for c-MET-JAK1/2-STAT3 signaling in KRASMT CRC that support the further clinical development of JAK/STAT3 or c-MET inhibitors in conjunction with MEK inhibition in KRASMT CRC tumours.
Original languageEnglish
Title of host publicationThe c-MET-JAK1/2-STAT3 signalling axis is regulated by ADAM17 and is a key mediator of resistance to MEK inhibition in KRAS mutant colorectal cancer
Place of PublicationProffered paper sessions
PublisherNational Cancer Research Institute
Publication statusPublished - Nov 2013

Fingerprint Dive into the research topics of 'The c-MET-JAK1/2-STAT3 signalling axis is regulated by ADAM17 and is a key mediator of resistance to MEK inhibition in KRAS mutant colorectal cancer'. Together they form a unique fingerprint.

  • Cite this

    Van Schaeybroeck, S., Kalimutho, M., Dunne, P., Moore, W., Jithesh, P., Fenning, C., Carson, R., Longley, D., & Johnston, P. (2013). The c-MET-JAK1/2-STAT3 signalling axis is regulated by ADAM17 and is a key mediator of resistance to MEK inhibition in KRAS mutant colorectal cancer. In The c-MET-JAK1/2-STAT3 signalling axis is regulated by ADAM17 and is a key mediator of resistance to MEK inhibition in KRAS mutant colorectal cancer National Cancer Research Institute.