MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

Andrea Lampis; Pietro Carotenuto; Georgios Vlachogiannis; Luciano Cascione; Somaieh Hedayat; Rosemary Burke; Paul Clarke; Else Bosma; Michele Simbolo; Aldo Scarpa; Sijia Yu; Rebecca Cole; Elizabeth Smyth; Javier Fernández Mateos; Ruwaida Begum; Blanka Hezelova; Zakaria Eltahir; Andrew Wotherspoon; Nicos Fotiadis; Maria Antonietta Bali; Chirag Nepal; Khurum Khan; Mark Stubbs; Jens C Hahne; Pierluigi Gasparini; Vincenza Guzzardo; Carlo M Croce; Suzanne Eccles; Matteo Fassan; David Cunningham; Jesper B Andersen; Paul Workman; Nicola Valeri; Chiara Braconi

doi:10.1053/j.gastro.2017.10.043

MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

Andrea Lampis, Pietro Carotenuto, Georgios Vlachogiannis, Luciano Cascione, Somaieh Hedayat, Rosemary Burke, Paul Clarke, Else Bosma, Michele Simbolo, Aldo Scarpa, Sijia Yu, Rebecca Cole, Elizabeth Smyth, Javier Fernández Mateos, Ruwaida Begum, Blanka Hezelova, Zakaria Eltahir, Andrew Wotherspoon, Nicos Fotiadis, Maria Antonietta BaliChirag Nepal, Khurum Khan, Mark Stubbs, Jens C Hahne, Pierluigi Gasparini, Vincenza Guzzardo, Carlo M Croce, Suzanne Eccles, Matteo Fassan, David Cunningham, Jesper B Andersen, Paul Workman, Nicola Valeri, Chiara Braconi

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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.

Originalsprog	Engelsk
Tidsskrift	Gastroenterology
Vol/bind	154
Udgave nummer	4
Sider (fra-til)	1066-1079
ISSN	0016-5085
DOI	https://doi.org/10.1053/j.gastro.2017.10.043
Status	Udgivet - mar. 2018

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10.1053/j.gastro.2017.10.043Licens: CC BY

MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in CholangiocarcinomaForlagets udgivne version, 5,96 MBLicens: CC BY

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Lampis, A., Carotenuto, P., Vlachogiannis, G., Cascione, L., Hedayat, S., Burke, R., Clarke, P., Bosma, E., Simbolo, M., Scarpa, A., Yu, S., Cole, R., Smyth, E., Mateos, J. F., Begum, R., Hezelova, B., Eltahir, Z., Wotherspoon, A., Fotiadis, N., ... Braconi, C. (2018). MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma. Gastroenterology, 154(4), 1066-1079. https://doi.org/10.1053/j.gastro.2017.10.043

Lampis, A, Carotenuto, P, Vlachogiannis, G, Cascione, L, Hedayat, S, Burke, R, Clarke, P, Bosma, E, Simbolo, M, Scarpa, A, Yu, S, Cole, R, Smyth, E, Mateos, JF, Begum, R, Hezelova, B, Eltahir, Z, Wotherspoon, A, Fotiadis, N, Bali, MA, Nepal, C, Khan, K, Stubbs, M, Hahne, JC, Gasparini, P, Guzzardo, V, Croce, CM, Eccles, S, Fassan, M, Cunningham, D, Andersen, JB, Workman, P, Valeri, N & Braconi, C 2018, 'MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma', Gastroenterology, bind 154, nr. 4, s. 1066-1079. https://doi.org/10.1053/j.gastro.2017.10.043

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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.",

keywords = "Journal Article",

author = "Andrea Lampis and Pietro Carotenuto and Georgios Vlachogiannis and Luciano Cascione and Somaieh Hedayat and Rosemary Burke and Paul Clarke and Else Bosma and Michele Simbolo and Aldo Scarpa and Sijia Yu and Rebecca Cole and Elizabeth Smyth and Mateos, {Javier Fern{\'a}ndez} and Ruwaida Begum and Blanka Hezelova and Zakaria Eltahir and Andrew Wotherspoon and Nicos Fotiadis and Bali, {Maria Antonietta} and Chirag Nepal and Khurum Khan and Mark Stubbs and Hahne, {Jens C} and Pierluigi Gasparini and Vincenza Guzzardo and Croce, {Carlo M} and Suzanne Eccles and Matteo Fassan and David Cunningham and Andersen, {Jesper B} and Paul Workman and Nicola Valeri and Chiara Braconi",

year = "2018",

month = mar,

doi = "10.1053/j.gastro.2017.10.043",

language = "English",

volume = "154",

pages = "1066--1079",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier",

number = "4",

}

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

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). 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.

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). 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.

KW - Journal Article

U2 - 10.1053/j.gastro.2017.10.043

DO - 10.1053/j.gastro.2017.10.043

M3 - Journal article

C2 - 29113809

SN - 0016-5085

VL - 154

SP - 1066

EP - 1079

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

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