Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention
Abstract Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient sam...
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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/s41408-025-01215-x |
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| author | Rodrigo Fonseca Yuan Xiao Zhu Laura A. Bruins Joseph Ahmann Cecilia de Bonolo Campos Esteban Braggio Xianfeng Chen Mariano Arribas Susie Darvish Seth Welsh Erin Meermeier Kiran K. Mangalaparthi Richard K. Kandasamy Greg Ahmann J. Erin Wiedmeier-Nutor Akhilesh Pandey Marta Chesi P. Leif Bergsagel Rafael Fonseca |
| author_facet | Rodrigo Fonseca Yuan Xiao Zhu Laura A. Bruins Joseph Ahmann Cecilia de Bonolo Campos Esteban Braggio Xianfeng Chen Mariano Arribas Susie Darvish Seth Welsh Erin Meermeier Kiran K. Mangalaparthi Richard K. Kandasamy Greg Ahmann J. Erin Wiedmeier-Nutor Akhilesh Pandey Marta Chesi P. Leif Bergsagel Rafael Fonseca |
| author_sort | Rodrigo Fonseca |
| collection | DOAJ |
| description | Abstract Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies. |
| format | Article |
| id | doaj-art-20eda5881b3a4ca5870e8917c7a646ea |
| 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-20eda5881b3a4ca5870e8917c7a646ea2025-02-09T12:13:03ZengNature Publishing GroupBlood Cancer Journal2044-53852025-02-0115111210.1038/s41408-025-01215-xExploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic interventionRodrigo Fonseca0Yuan Xiao Zhu1Laura A. Bruins2Joseph Ahmann3Cecilia de Bonolo Campos4Esteban Braggio5Xianfeng Chen6Mariano Arribas7Susie Darvish8Seth Welsh9Erin Meermeier10Kiran K. Mangalaparthi11Richard K. Kandasamy12Greg Ahmann13J. Erin Wiedmeier-Nutor14Akhilesh Pandey15Marta Chesi16P. Leif Bergsagel17Rafael Fonseca18Division of Internal MedicineDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo ClinicDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDepartment of Laboratory Medicine and Pathology, Mayo ClinicDepartment of Laboratory Medicine and Pathology, Mayo ClinicDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDepartment of Laboratory Medicine and Pathology, Mayo ClinicDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyDivision of Hematology and Medical OncologyAbstract Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies.https://doi.org/10.1038/s41408-025-01215-x |
| spellingShingle | Rodrigo Fonseca Yuan Xiao Zhu Laura A. Bruins Joseph Ahmann Cecilia de Bonolo Campos Esteban Braggio Xianfeng Chen Mariano Arribas Susie Darvish Seth Welsh Erin Meermeier Kiran K. Mangalaparthi Richard K. Kandasamy Greg Ahmann J. Erin Wiedmeier-Nutor Akhilesh Pandey Marta Chesi P. Leif Bergsagel Rafael Fonseca Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention Blood Cancer Journal |
| title | Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention |
| title_full | Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention |
| title_fullStr | Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention |
| title_full_unstemmed | Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention |
| title_short | Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention |
| title_sort | exploring bcl2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma potential avenues for therapeutic intervention |
| url | https://doi.org/10.1038/s41408-025-01215-x |
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