Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistan...

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Autores principales:	Federica Frezzato, Andrea Visentin, Filippo Severin, Serena Pizzo, Edoardo Ruggeri, Nayla Mouawad, Leonardo Martinello, Elisa Pagnin, Valentina Trimarco, Alessia Tonini, Samuela Carraro, Stefano Pravato, Silvia Imbergamo, Sabrina Manni, Francesco Piazza, Anna Maria Brunati, Monica Facco, Livio Trentin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chronic lymphocytic leukemia Ibrutinib HSP70 HSF1 drug-resistance phenols Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3b7ce646fe2c43e68124326c729c449c
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spelling	oai:doaj.org-article:3b7ce646fe2c43e68124326c729c449c2021-11-11T15:33:29ZTargeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia10.3390/cancers132154532072-6694https://doaj.org/article/3b7ce646fe2c43e68124326c729c449c2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5453https://doaj.org/toc/2072-6694The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.Federica FrezzatoAndrea VisentinFilippo SeverinSerena PizzoEdoardo RuggeriNayla MouawadLeonardo MartinelloElisa PagninValentina TrimarcoAlessia ToniniSamuela CarraroStefano PravatoSilvia ImbergamoSabrina ManniFrancesco PiazzaAnna Maria BrunatiMonica FaccoLivio TrentinMDPI AGarticlechronic lymphocytic leukemiaIbrutinibHSP70HSF1drug-resistancephenolsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5453, p 5453 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic lymphocytic leukemia Ibrutinib HSP70 HSF1 drug-resistance phenols Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	chronic lymphocytic leukemia Ibrutinib HSP70 HSF1 drug-resistance phenols Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Federica Frezzato Andrea Visentin Filippo Severin Serena Pizzo Edoardo Ruggeri Nayla Mouawad Leonardo Martinello Elisa Pagnin Valentina Trimarco Alessia Tonini Samuela Carraro Stefano Pravato Silvia Imbergamo Sabrina Manni Francesco Piazza Anna Maria Brunati Monica Facco Livio Trentin Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
description	The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.
format	article
author	Federica Frezzato Andrea Visentin Filippo Severin Serena Pizzo Edoardo Ruggeri Nayla Mouawad Leonardo Martinello Elisa Pagnin Valentina Trimarco Alessia Tonini Samuela Carraro Stefano Pravato Silvia Imbergamo Sabrina Manni Francesco Piazza Anna Maria Brunati Monica Facco Livio Trentin
author_facet	Federica Frezzato Andrea Visentin Filippo Severin Serena Pizzo Edoardo Ruggeri Nayla Mouawad Leonardo Martinello Elisa Pagnin Valentina Trimarco Alessia Tonini Samuela Carraro Stefano Pravato Silvia Imbergamo Sabrina Manni Francesco Piazza Anna Maria Brunati Monica Facco Livio Trentin
author_sort	Federica Frezzato
title	Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
title_short	Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
title_full	Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
title_fullStr	Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
title_full_unstemmed	Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia
title_sort	targeting of hsp70/hsf1 axis abrogates in vitro ibrutinib-resistance in chronic lymphocytic leukemia
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3b7ce646fe2c43e68124326c729c449c
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Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

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