TY - JOUR
T1 - Predictive signatures inform the effective repurposing of decitabine to treat KRAS-dependent pancreatic ductal adenocarcinoma
AU - Mottini, Carla
AU - Tomihara, Hideo
AU - Carrella, Diego
AU - Lamolinara, Alessia
AU - Iezzi, Manuela
AU - Huang, Justin K.
AU - Amoreo, Carla A.
AU - Buglioni, Simonetta
AU - Manni, Isabella
AU - Robinson, Frederick S.
AU - Minelli, Rosalba
AU - Kang, Ya'an
AU - Fleming, Jason B.
AU - Kim, Michael P.
AU - Bristow, Christopher A.
AU - Trisciuoglio, Daniela
AU - Iuliano, Antonella
AU - Bufalo, Donatella Del
AU - Bernardo, Diego Di
AU - Melisi, Davide
AU - Draetta, Giulio F.
AU - Ciliberto, Gennaro
AU - Carugo, Alessandro
AU - Cardone, Luca
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-0187
DO - 10.1158/0008-5472.CAN-19-0187
M3 - Article
C2 - 31492820
AN - SCOPUS:85072829186
SN - 0008-5472
VL - 79
SP - 5612
EP - 5625
JO - Cancer research
JF - Cancer research
IS - 21
ER -