Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax
Abstract Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relaps...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01214-y |
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| author | Caroline A. Coughlin Dhanvantri Chahar Marianna Lekakis Abdessamad A. Youssfi Lingxiao Li Evan Roberts Natalia Campos Gallego Claude-Henry Volmar Ola Landgren Shaun Brothers Anthony J. Griswold Catalina Amador Daniel Bilbao Francesco Maura Jonathan H. Schatz |
| author_facet | Caroline A. Coughlin Dhanvantri Chahar Marianna Lekakis Abdessamad A. Youssfi Lingxiao Li Evan Roberts Natalia Campos Gallego Claude-Henry Volmar Ola Landgren Shaun Brothers Anthony J. Griswold Catalina Amador Daniel Bilbao Francesco Maura Jonathan H. Schatz |
| author_sort | Caroline A. Coughlin |
| collection | DOAJ |
| description | Abstract Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently. |
| format | Article |
| id | doaj-art-3511edc319564002b5706a04c0b6b203 |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-3511edc319564002b5706a04c0b6b2032025-02-09T12:13:05ZengNature Publishing GroupBlood Cancer Journal2044-53852025-02-0115111410.1038/s41408-025-01214-yBruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclaxCaroline A. Coughlin0Dhanvantri Chahar1Marianna Lekakis2Abdessamad A. Youssfi3Lingxiao Li4Evan Roberts5Natalia Campos Gallego6Claude-Henry Volmar7Ola Landgren8Shaun Brothers9Anthony J. Griswold10Catalina Amador11Daniel Bilbao12Francesco Maura13Jonathan H. Schatz14University of Miami Miller School of Medicine Medical Scientist Training ProgramDivision of Hematology, Department of Medicine, University of Miami Miller School of MedicineDivision of Hematology, Department of Medicine, University of Miami Miller School of MedicineDivision of Hematology, Department of Medicine, University of Miami Miller School of MedicineGenScript ProBioSylvester Comprehensive Cancer CenterSylvester Comprehensive Cancer CenterCenter for Therapeutic Innovation, University of MiamiSylvester Comprehensive Cancer CenterCenter for Therapeutic Innovation, University of MiamiJohn P. Hussman Institute for Human Genomics, University of Miami Miller School of MedicineSylvester Comprehensive Cancer CenterSylvester Comprehensive Cancer CenterSylvester Comprehensive Cancer CenterDivision of Hematology, Department of Medicine, University of Miami Miller School of MedicineAbstract Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.https://doi.org/10.1038/s41408-025-01214-y |
| spellingShingle | Caroline A. Coughlin Dhanvantri Chahar Marianna Lekakis Abdessamad A. Youssfi Lingxiao Li Evan Roberts Natalia Campos Gallego Claude-Henry Volmar Ola Landgren Shaun Brothers Anthony J. Griswold Catalina Amador Daniel Bilbao Francesco Maura Jonathan H. Schatz Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax Blood Cancer Journal |
| title | Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax |
| title_full | Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax |
| title_fullStr | Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax |
| title_full_unstemmed | Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax |
| title_short | Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax |
| title_sort | bruton s tyrosine kinase inhibition re sensitizes multidrug resistant dlbcl tumors driven by bcl10 gain of function mutants to venetoclax |
| url | https://doi.org/10.1038/s41408-025-01214-y |
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