Our strategy builds on previous work demonstrating that smaller gene-editing libraries can be used to define which tumor suppressors are important for ICC initiation and build on a substantial body of work identifying which oncogenes are essential for the formation of cancer cells in the liver (26), particularly KRas, which has previously been used to define the responsiveness to MEK inhibition in ICC (45). This evidence concerns the gene KRAS and intrahepatic cholangiocarcinoma.