About 90% pancreatic cancer arises in the ducts ofthe pancreas and thus is called pancreatic ductal adenocarcinoma (PDAC). PDAC malignancy is aggressive and difficult to treat. 85% PDAC patients are at late stage upon diagnosis and surgical removal is not applicable. So far, traditional chemo drug gemtacibine is still the best and first choice for late stage PDAC, but only 15% patients are sensitive to the drug.

Loss of function in SMAD4 gene is the driver for 55% PDAC. In 10-30% PDAC, SMAD4 locus along with the neighboring genes such as ME2 is deleted from the genome. ME2 is from the three-membered malic enzyme family, catalyzing the reaction from malate to pyruvate. In most tissues, ME1 and ME2 are the working horses in the family, while ME3 level is very low and is believed dispensable for cell life. However, in SMAD4-ME2 null PDAC cells, ME3 level is enhanced, for the purpose to compensate for ME2absence, as ME3 knockdown or knockout did cause massive cell death. So, when treating these PDAC cells, collateral lethality could be achieved if ME3 activity is down-regulated by its inhibitors.