|
|||||
|
|
BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers |
|
| Authors: | Marialuisa Lavitrano Leonarda Ianzano Sara Bonomo Annamaria Cialdella Maria Grazia Cerrito Fabio Pisano Carola Missaglia Roberto Giovannoni Gabriele Romano Chelsea M McLean Emile E Voest Filomena D'Amato Barbara Noli Gian Luca Ferri Marco Agostini Salvatore Pucciarelli Kristian Helin Biagio E Leone Vincenzo Canzonieri Emanuela Grassilli |
| Affiliation: | 1. School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy;2. Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;3. NEF-Laboratory, Department of Biomedical Science, University of Cagliari, Cagliari, Italy;4. First Surgical Clinic Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA;5. First Surgical Clinic Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy;6. Center for Epigenetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA;7. Pathology Unit and CRO Biobank, CRO Aviano National Cancer Institute, Aviano, Italy |
| 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. |
| Keywords: | colon cancer p65BTK BTK inhibitors drug-resistance TP53 |