Abstract
Mutated KRAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic KRAS are still under investigation or awaiting clinical approval. Using a specific KRAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic KRAS. We identified and validated decitabine, an FDA-approved drug, as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed KRAS dependency. Mechanistically, decitabine efficacy was linked to KRAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in KRAS-dependent tumors cells. These findings also showed that gene signatures related to KRAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of patients with KRAS-mutated pancreatic cancer. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant KRAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease. SIGNIFICANCE: Decitabine is a promising drug for cancer cells dependent on RAS signaling.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest epithelial tumors, with an overall 5-year survival rate of only 8% [1]
We took advantage of previously validated KRAS–specific gene expression signatures generated in different isogenic, not-transformed Human pancreatic ductal epithelia (HPDE) cell lines carrying the overexpression of KRASG12V oncogene (Materials and Methods)
Decitabine treatment induced cellular senescence in HPDE-KRASG12V cells but not in isogenic wild-type cells, as demonstrated by the increase of b-galactosidase (b-gal staining; Supplementary Fig. S1E). This observation was in line with previous data reporting that the inhibition of senescence by oncogenic KRAS in HPDE can be prevented by decitabine treatment in pancreatic intraepithelial neoplasia (PanIN) models [36, 37]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest epithelial tumors, with an overall 5-year survival rate of only 8% [1]. The RAS gene family includes KRAS, N-RAS, and H-RAS genes, and the oncogenic mutation in residues G12, G13, and Q61, which are the most common lesions in human tumors [7]. These mutations compromise GTPase activity, inducing constitutive RAS signaling that results in abnormal proliferation and tumor growth [8]. In PDAC, the most frequent point mutation is located at codon G12 of KRAS and leads to the activation of molecular pathways supporting tumor initiation, development, and maintenance [4, 8,9,10]
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