Here, we sought to determine the therapeutic potential of MEK inhibitors in a panel of human iCCA cell lines as well as in a novel mouse iCCA preclinical model characterized by the concomitant activation of K-RasG12D mutant allele and overexpression of an activated/cleaved form of Notch1 (NICD) (K-Ras/NICD). Here, NOTCH1 is linked to infantile convulsions and choreoathetosis.