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

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, Kristian Helin, Biagio E. Leone, Vincenzo Canzonieri, Emanuela Grassilli

Research output: Contribution to journalArticlepeer-review

Abstract

Colorectal cancer (CRC) 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.

Original languageEnglish
Pages (from-to)134-147
Number of pages14
JournalJournal of Pathology
Volume250
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

Keywords

  • BTK inhibitors
  • colon cancer
  • drug-resistance
  • p65BTK
  • TP53

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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