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

Lavitrano, Marialuisa;Ianzano, Leonarda;Bonomo, Sara;Cialdella, Annamaria;Cerrito, Maria Grazia;Pisano, Fabio;Missaglia, Carola;Giovannoni, Roberto;Romano, Gabriele;McLean, Chelsea M;Voest, Emile E;D'Amato, Filomena

Methodology

;Noli, Barbara

Resources

;Ferri, Gian Luca

Methodology

;Agostini, Marco;Pucciarelli, Salvatore;Helin, Kristian;Leone, Biagio Eugenio;Canzonieri, Vincenzo;Grassilli, Emanuela

2020-01-01

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Abstract

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.