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 cytotoxic drug treatment, we combined microarray data from isogenic in vivo Kras wild type (WT) and MT CRC models, KrasWT/MT primary tumours, pre-treatment metastatic CRC liver biopsies and drug resistant and sensitive CRC cell lines.
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 chemotherapy or MEK inhibitors resulted in significant increases in JAK2-STAT3 activity in KrasMT in vitro and in vivo models that sensitized KrasMT CRC cells to RNAi- or small molecule-mediated inhibition of this pathway and resulted in synergistic increases in cell death. Importantly, combined JAK1/2-MEK1/2 inhibition in KrasMT xenografts led to dramatically attenuated tumour growth and increased survival. In addition, we identified c-MET as upstream receptor tyrosine kinase mediating STAT3 activity and c-MET RNAi- or small molecule-mediated inhibition resulted in potent increase in apoptosis in KrasMT CRC.
In summary, using a systems biology approach, we have identified an essential role for cMET-JAK1/2-STAT3 signaling in KrasMT CRC that support the further clinical development of JAK/STAT3 or c-MET inhibitors in conjunction with chemotherapy or MEK inhibition in KrasMT CRC tumours.
|Title of host publication||The c-MET-JAK1/2-STAT3 signalling axis is a critical mediator of drug resistance in Kras mutant colorectal cancer|
|Place of Publication||Proffered paper sessions|
|Publisher||National Cancer Research Institute|
|Publication status||Published - Nov 2012|