1. BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers
- Author
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Fabio Pisano, Marialuisa Lavitrano, Gian-Luca Ferri, Filomena D'Amato, Emile E. Voest, Marco Agostini, Sara Bonomo, Annamaria Cialdella, Carola Missaglia, Gabriele Romano, Maria Grazia Cerrito, Kristian Helin, Roberto Giovannoni, Emanuela Grassilli, Vincenzo Canzonieri, Biagio Eugenio Leone, Barbara Noli, Leonarda Ianzano, Salvatore Pucciarelli, Chelsea M. McLean, Lavitrano, M, Ianzano, L, Bonomo, S, Cialdella, A, Cerrito, M, Pisano, F, Missaglia, C, Giovannoni, R, Romano, G, Mclean, C, Voest, E, D'Amato, F, Noli, B, Ferri, G, Agostini, M, Pucciarelli, S, Helin, K, Leone, B, Canzonieri, V, Grassilli, E, 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 E, Canzonieri, Vincenzo, and Grassilli, Emanuela
- Subjects
0301 basic medicine ,Colorectal cancer ,medicine.medical_treatment ,Mice, Nude ,Apoptosis ,Drug resistance ,Pathology and Forensic Medicine ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,drug-resistance ,Antineoplastic Combined Chemotherapy Protocols ,Agammaglobulinaemia Tyrosine Kinase ,Tumor Cells, Cultured ,Gene silencing ,Medicine ,Animals ,Humans ,Protein Isoforms ,Molecular Targeted Therapy ,TP53 ,Protein Kinase Inhibitors ,Neoplasm Staging ,Chemotherapy ,business.industry ,BTK inhibitor ,Cancer ,Drug Synergism ,medicine.disease ,Genes, p53 ,Xenograft Model Antitumor Assays ,E2F Transcription Factors ,Organoids ,BTK inhibitors ,030104 developmental biology ,colon cancer ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Disease Progression ,Fluorouracil ,p65BTK ,business ,Tyrosine kinase ,Colon cancer - 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.
- Published
- 2020