Combination of CS2164 and Venetoclax Shows Synergistic Antitumor Effect in High-Grade B-Cell Lymphomas with ConcomitantMYCandBCL2Rearrangements

Abstract

High-grade B-cell lymphoma with concurrentMYCandBCL2rearrangements (HGBCL-DHL) is a rare and aggressive B-cell disorder with a high likelihood of nonresponsiveness to the front-line immunochemotherapy. Patients with HGBCL-DHL who develop a recurrent or progressive disease have limited effective therapeutics and show very poor clinical outcomes. Therefore, it calls for the development of novel targeted therapies for this specific patient populations. In this study, we showed that combination of BCL2 inhibitor venetoclax and CS2164, a novel orally active multitarget inhibitor, is a potent therapeutic strategy against HGBCL-DHL in the preclinical setting. BCL2rearrangement, a hallmark feature of HGBCL-DHL, often results in increased BCL2 protein that counteracts the proapoptotic proteins of BCL2 family, and thus blocks cell death. BCL2 blockage with venetoclax shows promising clinical responses in various human malignancies. However, resistance to venetoclax takes place following its continuous administration, suggesting that venetoclax should combine with other agents to prevent disease progression. CS2164 is originally developed by China and designed to perturb three key characteristics of neoplasms: tumor angiogenesis, cell mitosis and chronic inflammation. Our previous study demonstrated that CS2164 exerted potently antilymphoma activities in MYC-driven lymphomas, providing evidence that CS2164 could potentiate the effect of venetoclax for MYC/BCL2 driven HGBCL-DHL. In the present work, we first observed that both venetoclax and CS2164 as single agent reduced the capability of cell proliferation in HGBCL-DHL cell lines. Next, we found that CS2164 synergized with venetoclax to suppress cell proliferation and trigger cell apoptosis in HGBCL-DHLin vitro. More importantly, when compared with each single drug groups, coadministration of venetoclax and CS2164 resulted in superior suppression of HGBCL-DHL cell growth and remarkably abrogated tumor burden in a HGBCL-DHL-xenografted mouse model. The synergistic lethality of venetoclax and CS2164 towards HGBCL-DHL cells was associated with the modulation of multiple molecular mechanisms. The underlying mechanisms for the synergy of the two drugs included the blockade of Rad51 recombinase-dependent DNA repair, the perturbation of the delicate balance of BCL2 family proteins that induced mitochondrial membrane depolarization and subsequently led to the proapoptotic effect, as well as the inhibition of PI3K/AKT/mTOR pathway and MYC expression. In summary, these findings suggest that the regimen of CS2164 and venetoclax combination is highly effective to eliminate HGBCL-DHL cellsin vitroandin vivoand thus provide a rational treatment paradigm to strip HGBCL-DHL of its protection fromMYCandBCL2rearrangements. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: CS2164 originally developed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.