Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

Carotenuto, P. et al. (2021) Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage. Nature Communications, 12, 6738. (doi: 10.1038/s41467-021-27099-6) (PMID:34795259) (PMCID:PMC8602334)

Abstract

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.

• Item Type: Articles
• Additional Information: N.V. is a recipient of a CRUK Career Development Award, a NIHR Royal Marsden/ICR Biomedical Research Centre Flagship Grant, and a Marie Curie Career Integration Grant from the European Union. P.C. is a current recipient of a Marie Skłodowska-Curie Career Re-Integration fellowship funded by AIRC and the European Union’s Horizon 2020 research and innovation programme (Grant agreement No 800924). N.B.J. is a current recipient of a Cancer Research UK Clinician Scientist Fellowship (grant C55370/A25813). A.S. is supported by Associazione Italiana Ricerca Cancro (AIRC 5x1000 n. 12182) and Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017). P.W. is supported by CRUK, Wellcome, Chordoma Foundation, Mark Foundation and Isa CRUK Life fellow. We acknowledge funding to the CRUK Cancer Therapeutics Unit at the Institute of Cancer Research (grant C2739/A22897) and findings to CRUK Centre at The Institute of Cancer Research.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Rae, Dr Colin and Chang, Professor David and Braconi, Professor Chiara and Biankin, Professor Andrew and Valeri, Dr Nicola and Upstill-Goddard, Dr Rosie and Amato, Francesco
• Authors: Carotenuto, P., Amato, F., Lampis, A., Rae, C., Hedayat, S., Previdi, M. C., Zito, D., Raj, M., Guzzardo, V., Sclafani, F., Lanese, A., Parisi, C., Vicentini, C., Said-Huntingford, I., Hahne, J. C., Hallsworth, A., Kirkin, V., Young, K., Begum, R., Wotherspoon, A., Kouvelakis, K., Azevedo, S. X., Michalarea, V., Upstill-Goddard, R., Rao, S., Watkins, D., Starling, N., Sadanandam, A., Chang, D. K., Biankin, A. V., Jamieson, N. B., Scarpa, A., Cunningham, D., Chau, I., Workman, P., Fassan, M., Valeri, N., and Braconi, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 6738
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301364		COMBINATION THERAPIES TARGETING IMMUNE EVASION IN PANCREATIC CANCER	Nigel Jamieson	Cancer Research UK (CRUK)	C55370/A25813	CS -Translational Research Centre