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BTK inhibitors synergize with 5-FU to treat drug-resistant TP53-null colon cancers

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Marialuisa Lavitrano
  • Leonarda Ianzano
  • Sara Bonomo
  • Annamaria Cialdella
  • Maria Grazia Cerrito
  • Fabio Pisano
  • Carola Missaglia
  • Roberto Giovannoni
  • Gabriele Romano
  • Chelsea M McLean
  • Emile E Voest
  • Filomena D'Amato
  • Barbara Noli
  • Gian Luca Ferri
  • Marco Agostini
  • Salvatore Pucciarelli
  • Helin, Kristian
  • Biagio Eugenio Leone
  • Vincenzo Canzonieri
  • Emanuela Grassilli

Colorectal cancer is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. This article is protected by copyright. All rights reserved.

OriginalsprogEngelsk
TidsskriftJournal of Pathology
Vol/bind250
Udgave nummer2
Sider (fra-til)134-147
Antal sider15
ISSN0022-3417
DOI
StatusUdgivet - feb. 2020

ID: 227413470