MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma
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MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma. / 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 Fernández; 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.
In: Gastroenterology, Vol. 154, No. 4, 03.2018, p. 1066-1079.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma
AU - Lampis, Andrea
AU - Carotenuto, Pietro
AU - Vlachogiannis, Georgios
AU - Cascione, Luciano
AU - Hedayat, Somaieh
AU - Burke, Rosemary
AU - Clarke, Paul
AU - Bosma, Else
AU - Simbolo, Michele
AU - Scarpa, Aldo
AU - Yu, Sijia
AU - Cole, Rebecca
AU - Smyth, Elizabeth
AU - Mateos, Javier Fernández
AU - Begum, Ruwaida
AU - Hezelova, Blanka
AU - Eltahir, Zakaria
AU - Wotherspoon, Andrew
AU - Fotiadis, Nicos
AU - Bali, Maria Antonietta
AU - Nepal, Chirag
AU - Khan, Khurum
AU - Stubbs, Mark
AU - Hahne, Jens C
AU - Gasparini, Pierluigi
AU - Guzzardo, Vincenza
AU - Croce, Carlo M
AU - Eccles, Suzanne
AU - Fassan, Matteo
AU - Cunningham, David
AU - Andersen, Jesper B
AU - Workman, Paul
AU - Valeri, Nicola
AU - Braconi, Chiara
N1 - Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2018/3
Y1 - 2018/3
N2 - 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, PDOs). 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 heatshockprotein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of PDOs 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 treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
AB - 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, PDOs). 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 heatshockprotein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of PDOs 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 treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
KW - Journal Article
U2 - 10.1053/j.gastro.2017.10.043
DO - 10.1053/j.gastro.2017.10.043
M3 - Journal article
C2 - 29113809
VL - 154
SP - 1066
EP - 1079
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 4
ER -
ID: 185472640