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

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 Eugenio Leone; Vincenzo Canzonieri; Emanuela Grassilli

doi:10.1002/path.5347

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

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 Eugenio Leone, Vincenzo Canzonieri, Emanuela Grassilli

6 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Pathology
ISSN	0022-3417
DOI	https://doi.org/10.1002/path.5347
Status	Udgivet - 1 feb. 2020

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10.1002/path.5347

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Lavitrano, M., Ianzano, L., Bonomo, S., Cialdella, A., Cerrito, M. G., Pisano, F., Missaglia, C., Giovannoni, R., Romano, G., McLean, C. M., Voest, E. E., D'Amato, F., Noli, B., Ferri, G. L., Agostini, M., Pucciarelli, S., Helin, K., Leone, B. E., Canzonieri, V., & Grassilli, E. (2020). BTK inhibitors synergize with 5-FU to treat drug-resistant TP53-null colon cancers. Journal of Pathology. https://doi.org/10.1002/path.5347

Lavitrano, M, Ianzano, L, Bonomo, S, Cialdella, A, Cerrito, MG, Pisano, F, Missaglia, C, Giovannoni, R, Romano, G, McLean, CM, Voest, EE, D'Amato, F, Noli, B, Ferri, GL, Agostini, M, Pucciarelli, S, Helin, K, Leone, BE, Canzonieri, V & Grassilli, E 2020, 'BTK inhibitors synergize with 5-FU to treat drug-resistant TP53-null colon cancers', Journal of Pathology. https://doi.org/10.1002/path.5347

@article{e2d59d7ffcaf4e298bfb0ba31ffcadd3,

title = "BTK inhibitors synergize with 5-FU to treat drug-resistant TP53-null colon cancers",

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.",

author = "Marialuisa Lavitrano and Leonarda Ianzano and Sara Bonomo and Annamaria Cialdella and Cerrito, {Maria Grazia} and Fabio Pisano and Carola Missaglia and Roberto Giovannoni and Gabriele Romano and McLean, {Chelsea M} and Voest, {Emile E} and Filomena D'Amato and Barbara Noli and Ferri, {Gian Luca} and Marco Agostini and Salvatore Pucciarelli and Kristian Helin and Leone, {Biagio Eugenio} and Vincenzo Canzonieri and Emanuela Grassilli",

year = "2020",

month = feb,

day = "1",

doi = "10.1002/path.5347",

language = "English",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "JohnWiley & Sons Ltd",

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TY - JOUR

T1 - BTK inhibitors synergize with 5-FU to treat drug-resistant TP53-null colon cancers

AU - Lavitrano, Marialuisa

AU - Ianzano, Leonarda

AU - Bonomo, Sara

AU - Cialdella, Annamaria

AU - Cerrito, Maria Grazia

AU - Pisano, Fabio

AU - Missaglia, Carola

AU - Giovannoni, Roberto

AU - Romano, Gabriele

AU - McLean, Chelsea M

AU - Voest, Emile E

AU - D'Amato, Filomena

AU - Noli, Barbara

AU - Ferri, Gian Luca

AU - Agostini, Marco

AU - Pucciarelli, Salvatore

AU - Helin, Kristian

AU - Leone, Biagio Eugenio

AU - Canzonieri, Vincenzo

AU - Grassilli, Emanuela

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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.

AB - 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.

U2 - 10.1002/path.5347

DO - 10.1002/path.5347

M3 - Journal article

C2 - 31518438

SN - 0022-3417

JO - Journal of Pathology

JF - Journal of Pathology

ER -

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

Abstract

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