Janus kinase (JAK) is one of the main upstream activators of signal transducers 
and activators of transcription (STAT) that are constitutively activated in 
various malignancies and are associated with cell growth, survival, and 
carcinogenesis. Here, we investigated the role of JAKs in colorectal cancer in 
order to develop effective therapeutic targets for INCB018424, which is the 
first JAK1/2 inhibitor to be approved by FDA. After examining the basal 
expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of 
INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell 
viability was determined using the trypan blue exclusion assay. The cell death 
mechanism was identified by the activation of caspase 3 using western blot and 
annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were 
cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both 
JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 
in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was 
proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes 
caspase-dependent cell death, which is prevented by treatment with z-VAD. The 
inhibition of JAK1 phosphorylation seemed sufficient to allow 
INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon 
cancer cell survival and the inhibition of JAK1 by INCB01424 results in 
caspase-dependent apoptosis in colorectal cancer cells. The use of selective 
JAK1 inhibitors could be an attractive therapy against colorectal cancer, but 
further clinical investigations are needed to test this possibility.