Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies
The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ se...
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2025-06-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/12114 |
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| author | Binu Kandathilparambil Sasi Chiara Tarantelli Stephen Martindale Elisa Civanelli Eleonora Cannas Giulio Sartori Alberto J. Arribas Stacey M. Fernandes Samantha J. Shupe John-Hanson Machado Svitlana Tyekucheva Yue Ren Michael Lahn Lars van der Veen Giusy Di Conza Francesco Bertoni Jennifer R. Brown |
| author_facet | Binu Kandathilparambil Sasi Chiara Tarantelli Stephen Martindale Elisa Civanelli Eleonora Cannas Giulio Sartori Alberto J. Arribas Stacey M. Fernandes Samantha J. Shupe John-Hanson Machado Svitlana Tyekucheva Yue Ren Michael Lahn Lars van der Veen Giusy Di Conza Francesco Bertoni Jennifer R. Brown |
| author_sort | Binu Kandathilparambil Sasi |
| collection | DOAJ |
| description |
The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ selective, non-ATP competitive inhibitor, roginolisib (IOA-244), in hematological malignancies including diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). To identify rational actionable combination partners that can be tested in hematologic malignancies, an unbiased pharmacological screening of 474 compounds was carried out in two lymphoma cell lines. We identified BCL2 blockade with venetoclax as synergistically active with roginolisib, a finding confirmed in a broad panel of lymphoma cell lines, DLBCL cell lines and primary CLL samples. We further demonstrate that the sensitizing effects of roginolisib to venetoclax correlate with suppression of downstream PI3K/AKT pathways and alterations in the expression of the apoptotic proteins BIM, mediated through FOXO1 transactivation, and MCL1, with ubiquitination and degradation mediated through GSK3α/β activation. These findings support proof of concept for roginolisib development in hematological malignancies as a single agent or in combination with venetoclax. A clinical trial of roginolisib with venetoclax and an anti-CD20 antibody is initiating in CLL.
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| format | Article |
| id | doaj-art-3b8f9cffd24f40cb8a622d03f9e26e71 |
| institution | DOAJ |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-3b8f9cffd24f40cb8a622d03f9e26e712025-08-20T03:21:42ZengFerrata Storti FoundationHaematologica0390-60781592-87212025-06-01999110.3324/haematol.2024.287180Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignanciesBinu Kandathilparambil Sasi0Chiara Tarantelli1Stephen Martindale2Elisa Civanelli3Eleonora Cannas4Giulio Sartori5Alberto J. Arribas6Stacey M. Fernandes7Samantha J. Shupe8John-Hanson Machado9Svitlana Tyekucheva10Yue Ren11Michael Lahn12Lars van der Veen13Giusy Di Conza14Francesco Bertoni15Jennifer R. Brown16Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MassachusettsInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; BellinzonaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MassachusettsInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; BellinzonaInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; BellinzonaInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; BellinzonaInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; BellinzonaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MassachusettsDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MassachusettsDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MassachusettsDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MassachusettsDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MassachusettsiOnctura SA; GenevaiOnctura BV; Amsterdam, NetherlandsiOnctura SA; GenevaInstitute of Oncology Research, Faculty of Biomedical Sciences, USI; Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale; BellinzonaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, Massachusetts, USA; Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Boston, MA The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ selective, non-ATP competitive inhibitor, roginolisib (IOA-244), in hematological malignancies including diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). To identify rational actionable combination partners that can be tested in hematologic malignancies, an unbiased pharmacological screening of 474 compounds was carried out in two lymphoma cell lines. We identified BCL2 blockade with venetoclax as synergistically active with roginolisib, a finding confirmed in a broad panel of lymphoma cell lines, DLBCL cell lines and primary CLL samples. We further demonstrate that the sensitizing effects of roginolisib to venetoclax correlate with suppression of downstream PI3K/AKT pathways and alterations in the expression of the apoptotic proteins BIM, mediated through FOXO1 transactivation, and MCL1, with ubiquitination and degradation mediated through GSK3α/β activation. These findings support proof of concept for roginolisib development in hematological malignancies as a single agent or in combination with venetoclax. A clinical trial of roginolisib with venetoclax and an anti-CD20 antibody is initiating in CLL. https://haematologica.org/article/view/12114 |
| spellingShingle | Binu Kandathilparambil Sasi Chiara Tarantelli Stephen Martindale Elisa Civanelli Eleonora Cannas Giulio Sartori Alberto J. Arribas Stacey M. Fernandes Samantha J. Shupe John-Hanson Machado Svitlana Tyekucheva Yue Ren Michael Lahn Lars van der Veen Giusy Di Conza Francesco Bertoni Jennifer R. Brown Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies Haematologica |
| title | Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| title_full | Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| title_fullStr | Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| title_full_unstemmed | Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| title_short | Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| title_sort | novel pi3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies |
| url | https://haematologica.org/article/view/12114 |
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