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BTK inhibitors synergise with 5‐FU to treat drug‐resistant TP53 ‐null colon cancers
Author(s) -
Lavitrano Marialuisa,
Ianzano Leonarda,
Bonomo Sara,
Cialdella Annamaria,
Cerrito Maria Grazia,
Pisano Fabio,
Missaglia Carola,
Giovani Roberto,
Romano Gabriele,
McLean Chelsea M,
Voest Emile E,
D'Amato Filomena,
Noli Barbara,
Ferri Gian Luca,
Agostini Marco,
Pucciarelli Salvatore,
Helin Kristian,
Leone Biagio E,
Canzonieri Vincenzo,
Grassilli Emanuela
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5347
Subject(s) - colorectal cancer , cancer research , gene silencing , apoptosis , drug resistance , bruton's tyrosine kinase , cancer , medicine , mouse model of colorectal and intestinal cancer , drug , tyrosine kinase , biology , pharmacology , receptor , genetics , gene
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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.