| Autor: |
Granau AM; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.; Rigshospitalet, Department of Hematology, University Hospital Copenhagen, 2100 Copenhagen, Denmark., Andersen PA; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.; Rigshospitalet, Department of Hematology, University Hospital Copenhagen, 2100 Copenhagen, Denmark., Jakobsen T; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark., Taouxi K; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark., Dalila N; Rigshospitalet, Department of Clinical Biochemistry, University Hospital Copenhagen, 2100 Copenhagen, Denmark., Mogensen JB; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark., Kristensen LS; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark., Grønbæk K; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.; Rigshospitalet, Department of Hematology, University Hospital Copenhagen, 2100 Copenhagen, Denmark.; Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health Sciences, University of Copenhagen, 1165 Copenhagen, Denmark., Dimopoulos K; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.; Rigshospitalet, Department of Clinical Biochemistry, University Hospital Copenhagen, 2100 Copenhagen, Denmark. |
| Abstrakt: |
Venetoclax, a BCL-2 inhibitor, has proven to be effective in several hematological malignancies, including mantle cell lymphoma (MCL). However, development of venetoclax resistance is inevitable and understanding its underlying molecular mechanisms can optimize treatment response. We performed a thorough genetic, epigenetic and transcriptomic analysis of venetoclax-sensitive and resistant MCL cell lines, also evaluating the role of the stromal microenvironment using human and murine co-cultures. In our model, venetoclax resistance was associated with abrogated TP53 activity through an acquired mutation and transcriptional downregulation leading to a diminished apoptotic response. Venetoclax-resistant cells also exhibited an upregulation of the PI3K/Akt pathway, and pharmacological inhibition of Akt and ERK with TIC-10 led to cell death in all venetoclax-resistant cell lines. Overall, we highlight the importance of targeted therapies, such as TIC-10, against venetoclax resistance-related pathways, which might represent future therapeutic prospects. |
