Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage
Authors: Pietro Carotenuto, Francesco Amato, Andrea Lampis, Colin Rae, Somaieh Hedayat, Maria C. Previdi, Domenico Zito, Maya Raj, Vincenza Guzzardo, Francesco Sclafani, Andrea Lanese, Claudia Parisi, Caterina Vicentini, Ian Said-Huntingford, Jens C. Hahne, Albert Hallsworth, Vladimir Kirkin, Kate Young, Ruwaida Begum, Andrew Wotherspoon, Kyriakos Kouvelakis, Sergio Xavier Azevedo, Vasiliki Michalarea, Rosie Upstill-Goddard, Sheela Rao, David Watkins, Naureen Starling, Anguraj Sadanandam, David K. Chang, Andrew V. Biankin, Nigel B. Jamieson, Aldo Scarpa, David Cunningham, Ian Chau, Paul Workman, Matteo Fassan, Nicola Valeri, Chiara Braconi
Sources: Nature Communications
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.