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


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Sandra Van Schaeybroeck1, Murugan Kalimutho1, Philip Dunne1, Wendy Allen1, Puthen Jithesh1, Cathy Fenning1, Robbie Carson1, Daniel Longley1, Patrick Johnston1
1Queen's University Belfast, Belfast, UK


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.


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.


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.


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.