CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With MYC and BCL2 Rearrangements.
Abstract
High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high
likelihood of treatment failure following front-line immunochemotherapies. Patients
with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic
strategies and show very poor clinical outcomes, thus calling for development of novel
therapies for this specific patient population. In this study, we investigated the
preclinical anti-lymphoma efficacies and potential mechanism of action of a novel
treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally
active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited
a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively
inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration
of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL
cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse
model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated
with induction of DNA damage and impairment of DNA repair ability. Of importance,
the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark
proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling
cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax
resistance, were significantly lessened in the presence of CS2164 and venetoclax,
thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating
the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen
of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical
setting, warranting further clinical investigations of this regimen for the treatment
of unfavorable HGBL-DHL patients.
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https://hdl.handle.net/10161/22479Published Version (Please cite this version)
10.3389/fonc.2021.618908Publication Info
Yuan, Delin; Li, Genhong; Yu, Lian; Jiang, Yuelong; Shi, Yuanfei; Chen, Qiulin; ...
Xu, Bing (2021). CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell
Lymphomas With MYC and BCL2 Rearrangements. Frontiers in oncology, 11. pp. 618908. 10.3389/fonc.2021.618908. Retrieved from https://hdl.handle.net/10161/22479.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ken H Young
Professor of Pathology
I am a clinically-oriented diagnostic physician with clinical expertise in the pathologic
diagnosis of hematologic cancers including tumors of the bone marrow, lymphoid tissue,
spleen and pre-malignant hematologic conditions. Another area of interest is blood
cancer classification with molecular and genetic profiling. In my research program,
we focus on molecular mechanisms of tumor progression, cell-of-origin, biomarkers,
and novel therapeutic strategies in lymphoma, myeloma and leukemia. In

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