Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells
Oncotarget, ISSN: 1949-2553, Vol: 7, Issue: 43, Page: 70000-70010
2016
- 57Citations
- 60Captures
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Metrics Details
- Citations57
- Citation Indexes57
- 57
- CrossRef43
- Captures60
- Readers60
- 60
Article Description
The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL. The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed. The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84994235708&origin=inward; http://dx.doi.org/10.18632/oncotarget.12132; http://www.ncbi.nlm.nih.gov/pubmed/27661108; https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.12132; https://dx.doi.org/10.18632/oncotarget.12132; https://www.oncotarget.com/article/12132/text/
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