Predictive signatures inform the effective repurposing of decitabine to treat KRAS-dependent pancreatic ductal adenocarcinoma

Carla Mottini, Hideo Tomihara, Diego Carrella, Alessia Lamolinara, Manuela Iezzi, Justin K. Huang, Carla A. Amoreo, Simonetta Buglioni, Isabella Manni, Frederick S. Robinson, Rosalba Minelli, Ya'an Kang, Jason B. Fleming, Michael P. Kim, Christopher A. Bristow, Daniela Trisciuoglio, Antonella Iuliano, Donatella Del Bufalo, Diego Di Bernardo, Davide MelisiGiulio F. Draetta, Gennaro Ciliberto, Alessandro Carugo, Luca Cardone

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5612-5625
Number of pages14
JournalCancer Research
Volume79
Issue number21
DOIs
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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