Targeting one of the genes selectively upregulated in LRCC, 3-phosphoinositide dependent protein kinase-1 (PDPK1), we demonstrate that the phenotype resistance to chemotherapy in pancreatic cancer LRCC can be abrogated as a potentially novel treatment avenue against this difficult to treat cell population possibly guiding novel combination therapies in this lethal disease. This evidence concerns the gene PDPK1 and hereditary leiomyomatosis and renal cell cancer.