Predictive signatures inform the effective repurposing of Decitabine to treat K-RAS-dependent Pancreatic Ductal Adenocarcinoma.

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ID: 40196
2019
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Abstract
Mutated K-RAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic K-RAS are still under investigation or awaiting clinical approval. Using a specific K-RAS-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 K-RAS. We identified and validated decitabine-a U.S. Food and Drug Administration-approved drug-as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed K-RAS dependency. Mechanistically, decitabine efficacy was linked to K-RAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in K-RAS-dependent tumors cells. These findings also showed that gene signatures related to K-RAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of K-RAS-mutated pancreatic cancer patients. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant K-RAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease.
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mottini2019predictivecancer Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Mottini, Carla;Tomihara, Hideo;Carrella, Diego;Lamolinara, Alessia;Iezzi, Manuela;Huang, Justin K;Amoreo, Carla A;Buglioni, Simonetta;Manni, Isabella;Robinson, Frederick S;Minelli, Rosalba;Kang, Ya'an;Fleming, Jason B;Kim, Michael P;Bristow, Christopher A;Trisciuoglio, Daniela;Iuliano, Antonella;Del Bufalo, Donatella;di Bernardo, Diego;Melisi, Davide;Draetta, Giulio F;Ciliberto, Gennaro;Carugo, Alessandro;Cardone, Luca;
Journal Cancer research
Year 2019
DOI
canres.0187.2019
URL
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