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.

Chidamide and venetoclax synergistically exert cytotoxicity on multiple myeloma by upregulating BIM expression

“…It has been reported that HDAC inhibitors could induce apoptosis through interference with cytoprotective DDR [40]. In addition, venetoclax can trigger DNA damage by weakening Rad51-meidiated DNA damage repair [41]. Thus, we hypothesized that the DNA damage induced by the combination of the two agents might contribute to the synergistic anti-myeloma effect of the two drugs.…”

HDAC Inhibitor and BCL2 Selective Inhibitor Synergistically Exert Cytotoxicity on Human Myeloma Cells by Upregulating BIM Expression

“…40 In addition, venetoclax can trigger DNA damage by weakening Rad51-meidiated DNA damage repair. 41 Thus, we hypothesized that the DNA damage induced by the combination of the two agents might contribute to the synergistic anti-myeloma effect of the two drugs. Accordingly, our results shown coexposure to chidamide and venetoclax led to a sharp increase of γH2A.X, a typical marker of DSB.…”

Targeting MYC-driven lymphoma: lessons learned and future directions

“…Deng et al observed a potential role of CS2164 for the treatment of NHLs through the perturbation of multiple signaling cascades (angiogenesis, inflammation and proliferation) by inhibiting the following kinases: vascular endothelial growth factor receptor 1-3 (VEGFR1, VEGFR2 and VEGFR3), platelet-derived growth factor receptor alpha (PDGFRα), receptor tyrosine kinase (c-Kit), kinase Aurora B (AURKB), and chronic inflammation-related kinase (CSF-1R). Specifically, CS2164 showed superior anti-lymphoma activity against MYC-arranged BL models, suggesting it could also have a cytotoxic effect on other MYC-altered malignancies [102] . Following these observations, Yuan et al [103] assessed the efficacy of this novel agent in combination with venetoclax using HGBL in vitro and in vivo models, where they could demonstrate a reduction of MYC and BCL2 protein levels, as well as antitumor efficacy with tolerable toxicities in a xenograft mouse model with MCA cells.…”