AZD4320 Is a Novel and Potent BCL-2/X_L Dual Inhibitor in Targeting Aggressive Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma. It is an incurable disease with frequent relapse from chemotherapies, targeted therapies, and cell therapies. Dysregulated expression of BCL-2 family members resulting in enhanced cell survival frequently occurs in many cancer types and often contributes to the development of therapeutic resistance. The BCL-2 inhibitor venetoclax has been shown to be effective in treating refractory/relapsed MCL patients. However, resistance often occurs and one of the underlying mechanisms of this resistance is the increased expression of other anti-apoptotic BCL-2 family members, such as BCL-X_L and MCL-1. In this study, we assessed the in vitro and in vivo efficacy of a novel and highly potent BCL-2/X_L dual inhibitor AZD4320 in preclinical models.

Methods: Cell viability assay was tested after 72-hour treatment with AZD4320 in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines by CellTiter-Glo (Promega). The assay was also done after a 24-hour treatment in primary PDX cells. Cell apoptosis assay was performed to determine if AZD4320 induces cell apoptosis in MCL cell lines. Furthermore, the in vivo efficacy of AZD4320 was assessed in a CAR-T resistant MCL patient-derived xenograft (PDX) model.

Results: AZD4320 significantly inhibited cell proliferation in all tested MCL cell lines, including both ibrutinib/venetoclax-sensitive and -resistant cell lines. It had an IC₅₀ value at a low nanomolar range between 0.59 nM to 18 nM. Consistently, AZD4320 was effective in targeting primary PDX cells ex vivo. AZD4320 induced cell apoptosis in a dose-dependent manner. AZD0466, the nanomedicine formulation of AZD4320 (30mg/kg, weekly, IV), dramatically inhibited tumor growth and prolonged mouse survival in an ibrutinib-CAR-T dual-resistant PDX mouse model. All mice tolerated the treatment dose without any body weight loss.

Conclusion: The novel BCL-2/X_L dual inhibitor AZD4320 demonstrated excellent anti-MCL activity in both ibrutinib/venetoclax-sensitive and -resistant MCL cells in vitro. This was further validated in vivo in a ibrutinib-CAR-T dual-resistant PDX model. These findings provide evidence that dual targeting of BCL-2 and BCL-X_L by AZD4320 is promising as it may overcome therapeutic resistance in relapsed/refractory MCL.