Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer

Irene Yushing Chong, Lauren Aronson, Hanna Bryant, Aditi Gulati, James Campbell, Richard Elliott, Stephen Pettitt, Paul Wilkerson, Maryou B Lambros, Jorge S Reis-Filho, Anisha Ramessur, Michael Davidson, Ian Chau, David Cunningham, Alan Ashworth, Christopher J Lord

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1780-1792
Number of pages13
JournalGut
Volume67
Issue number10
Early online date22 Aug 2017
DOIs
Publication statusPublished - Oct 2018

Keywords

  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Drug Discovery/methods
  • Esophageal Neoplasms/drug therapy
  • Humans
  • Pharmacogenetics
  • Pharmacogenomic Testing/methods
  • Proto-Oncogene Proteins c-myc/genetics
  • Pyrazoles/pharmacology
  • Pyrimidines/pharmacology
  • RNA Interference/drug effects
  • Receptor, ErbB-2/genetics
  • Signal Transduction/genetics
  • Xenograft Model Antitumor Assays

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