dc.contributor.author | Chong, IY | |
dc.contributor.author | Aronson, L | |
dc.contributor.author | Bryant, H | |
dc.contributor.author | Gulati, A | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Elliott, R | |
dc.contributor.author | Pettitt, S | |
dc.contributor.author | Wilkerson, P | |
dc.contributor.author | Lambros, MB | |
dc.contributor.author | Reis-Filho, JS | |
dc.contributor.author | Ramessur, A | |
dc.contributor.author | Davidson, M | |
dc.contributor.author | Chau, I | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2017-08-29T11:06:16Z | |
dc.date.issued | 2018-10-01 | |
dc.identifier.citation | Gut, 2018, 67 (10), pp. 1780 - 1792 | |
dc.identifier.issn | 0017-5749 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/796 | |
dc.identifier.eissn | 1468-3288 | |
dc.identifier.doi | 10.1136/gutjnl-2017-314408 | |
dc.description.abstract | OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. RESULTS: By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. CONCLUSIONS: BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453). TRIAL REGISTRATION NUMBER: NCT02884453; Pre-results. | |
dc.format | Print-Electronic | |
dc.format.extent | 1780 - 1792 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BMJ PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Esophageal Neoplasms | |
dc.subject | Pyrazoles | |
dc.subject | Pyrimidines | |
dc.subject | Receptor, erbB-2 | |
dc.subject | Proto-Oncogene Proteins c-myc | |
dc.subject | Antineoplastic Agents | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Pharmacogenetics | |
dc.subject | Signal Transduction | |
dc.subject | RNA Interference | |
dc.subject | Drug Discovery | |
dc.subject | Pharmacogenomic Testing | |
dc.title | Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1136/gutjnl-2017-314408 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-10 | |
rioxxterms.type | Other | |
dc.relation.isPartOf | Gut | |
pubs.issue | 10 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 67 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Ashworth Collaborators | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Chong, Yu-Shing | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Lord, Christopher | |