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.

Lavitrano, M., Ianzano, L., Bonomo, S., Cialdella, A., Cerrito, M., Pisano, F., et al. (2020). BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers. JOURNAL OF PATHOLOGY, 250(2), 134-147 [10.1002/path.5347].

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

Lavitrano, Marialuisa
;
Ianzano, Leonarda;Bonomo, Sara;Cerrito, Maria Grazia;Giovannoni, Roberto;Romano, Gabriele;NOLI, BARBARA;Leone, Biagio Eugenio;Grassilli, Emanuela
2020

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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Articolo in rivista - Articolo scientifico
BTK inhibitors; colon cancer; drug-resistance; p65BTK; TP53;
English
134
147
14
First published: 13 September 2019 Online Version of Record before inclusion in an issue
Lavitrano, M., Ianzano, L., Bonomo, S., Cialdella, A., Cerrito, M., Pisano, F., et al. (2020). BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers. JOURNAL OF PATHOLOGY, 250(2), 134-147 [10.1002/path.5347].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/242487
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