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.

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

Giovannoni, Roberto;
2019-01-01

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.
2019
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; Noli, Barbara; Ferri, Gian Luca; Agostini, Marco; Pucciarelli, Salvatore; Helin, Kristian; Leone, Biagio Eugenio; Canzonieri, Vincenzo; Grassilli, Emanuela
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1005280
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