Lampis, A., Carotenuto, P., Vlachogiannis, G., Cascione, L., Hedayat, S., Burke, R., Clarke, P., Bosma, E., Simbolo, M., Scarpa, A., Yu, S. J., Cole, R., Smyth, E., Mateos, J. F., Begum, R., Hezelova, B., Eltahir, Z., Wotherspoon, A., Fotiadis, N., Bali, M. A., Nepal, C., Khan, K., Stubbs, M., Hahne, J. C., Gasparini, P., Guzzardo, V., Croce, C. M., Eccles, S., Fassan, M., Cunningham, D., Andersen, J. B., Workman, P., Valeri, N., Braconi, C. (2018) MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. GASTROENTEROLOGY, 154 (4). pp. 1066-1079. ISSN 0016-5085

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Abstract

BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.

Item Type:	Article
Authors (ICR Faculty only):	Valeri, Nicola and Workman, Paul and Cunningham, David and Eccles, Sue
All Authors:	Lampis, A., Carotenuto, P., Vlachogiannis, G., Cascione, L., Hedayat, S., Burke, R., Clarke, P., Bosma, E., Simbolo, M., Scarpa, A., Yu, S. J., Cole, R., Smyth, E., Mateos, J. F., Begum, R., Hezelova, B., Eltahir, Z., Wotherspoon, A., Fotiadis, N., Bali, M. A., Nepal, C., Khan, K., Stubbs, M., Hahne, J. C., Gasparini, P., Guzzardo, V., Croce, C. M., Eccles, S., Fassan, M., Cunningham, D., Andersen, J. B., Workman, P., Valeri, N., Braconi, C.
Additional Information:	ISI Document Delivery No.: FZ2ZG Times Cited: 0 Cited Reference Count: 63 Lampis, Andrea Carotenuto, Pietro Vlachogiannis, Georgios Cascione, Luciano Hedayat, Somaieh Burke, Rosemary Clarke, Paul Bosma, Else Simbolo, Michele Scarpa, Aldo Yu, Sijia Cole, Rebecca Smyth, Elizabeth Mateos, Javier Fernandez Begum, Ruwaida Hezelova, Blanka Eltahir, Zakaria Wotherspoon, Andrew Fotiadis, Nicos Bali, Maria Antonietta Nepal, Chirag Khan, Khurum Stubbs, Mark Hahne, Jens C. Gasparini, Pierluigi Guzzardo, Vincenza Croce, Carlo M. Eccles, Suzanne Fassan, Matteo Cunningham, David Andersen, Jesper B. Workman, Paul Valeri, Nicola Braconi, Chiara braconi, chiara/0000-0003-4835-1259; Scarpa, Aldo/0000-0003-1678-739X; Simbolo, Michele/0000-0002-0866-4499 Institute of Cancer Research Clinician Scientist Fellowship; European Union; Pancreatic Cancer Action; NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre project grant; CRUK Career Development Award; NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre Flagship Grant; Marie Curie Career Integration Grant from the European Union; Associazione Italiana Ricerca sul Cancro (AIRC) [12182]; Novo Nordisk Foundation Hallas-Moller fellowship; Danish Medical Research Council (DFF); Cancer Research UK Chiara Braconi is the recipient of an Institute of Cancer Research Clinician Scientist Fellowship, a Marie Curie Career Integration Grant from the European Union, an Early Diagnosis Award from Pancreatic Cancer Action, and a NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre project grant. Nicola Valeri is a recipient of a CRUK Career Development Award, a NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre Flagship Grant, and a Marie Curie Career Integration Grant from the European Union. Aldo Scarpa is a recipient of an Associazione Italiana Ricerca sul Cancro (AIRC) grant no. 12182. Jesper B. Andersen holds a Novo Nordisk Foundation Hallas-Moller fellowship. Chirag Nepal holds a postdoctoral fellowship from the Danish Medical Research Council (DFF). We acknowledge Cancer Research UK funding to the Cancer Research UK Cancer Therapeutics Unit at the Institute of Cancer Research. Paul Workman is a Cancer Research UK Life Fellow. 0 W b saunders co-elsevier inc Philadelphia 1528-0012
Uncontrolled Keywords:	Organoid AUY922 Bile Duct Cancer DNAJB5 biliary-tract cancer tyrosine kinase inhibitors advanced solid tumors i dose-escalation pancreatic-cancer intrahepatic cholangiocarcinoma acquired-resistance microrna expression hsp90 inhibitors prostate-cancer Gastroenterology & Hepatology
Research teams:	ICR divisions > Cancer Therapeutics > Tumour Biology & Metastasis ICR divisions > Cancer Therapeutics > Signal Transduction & Molecular Pharmacology ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) Clinical Units > Gastrointestinal Unit ICR divisions > Molecular Pathology > Gastrointestinal Cancer Biology and Genomics
Depositing User:	Barry Jenkins
Date Deposited:	25 Apr 2018 13:47
Last Modified:	25 Apr 2018 13:47
URI:	http://publications.icr.ac.uk/id/eprint/16726

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