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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Mottini C,Tomihara H,Carrella D,Lamolinara A,Iezzi M,Huang JK,Amoreo CA,Buglioni S,Manni I,Robinson FS,Minelli R,Kang Y,Fleming JB,Kim MP,Bristow CA,Trisciuoglio D,Iuliano A,Del Bufalo D,Di Bernardo D,Melisi D,Dradoi
10.1158/0008-5472.CAN-19-0187subject
Has Abstractpub_date
2019-11-01 00:00:00pages
5612-5625issue
21eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-0187journal_volume
79pub_type
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