Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-XL), and myeloid cell leukemia-1 (MCL-1) is highly common in MCL. This renders these BCL-2 family members attractive targets for therapy; indeed, the BCL-2 inhibitor venetoclax (ABT-199), which already received FDA approval for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), shows promising results in early clinical trials for MCL. However, a significant subset of patients show primary resistance or will develop resistance upon prolonged treatment. Here, we describe the underlying mechanisms of venetoclax resistance in MCL, such as upregulation of BCL-XL or MCL-1, and the recent (clinical) progress in the development of inhibitors for these BCL-2 family members, followed by the transcriptional and (post-)translational (dys)regulation of the BCL-2 family proteins, including the role of the lymphoid organ microenvironment. Based upon these insights, we discuss how rational combinations of venetoclax with other therapies can be exploited to prevent or overcome venetoclax resistance and improve MCL patient outcome.

Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation

“…To investigate the mechanism(s) through which loss of CK2 activity sensitizes MCL cells to venetoclax, we evaluated changes in protein levels of BCL-2, MCL-1, and BCL-X L . The ratio of expression of BCL-2 over MCL-1 and BCL-X L combined has been described as an important determinant of venetoclax sensitivity in MCL, 3 , 16 , 17 and also corresponds with venetoclax sensitivity in the cell lines used in this study ( Figure 1B ). Both CK2 silencing and inhibition resulted in markedly reduced MCL-1 levels in MCL cells, wheras BCL-2 and BCL-X L protein levels were unaffected ( Figure 5A , B; Online Supplementary Figure S6A ).…”

“…Microenvironment-mediated drug resistance is commonly observed in MCL, also for venetoclax. 3 , 16 Direct contact with other cells in the lymph node and bone marrow (cell adhesion-mediated drug resistance), as well as paracrine soluble factors such as cytokines and chemokines result in reduced drug efficacy. To study microenvironment-mediated venetoclax resistance, we co-cultured MCL cell lines with the bone marrow stromal cell line HS-27a in the presence of venetoclax.…”

“…Elevated MCL-1, and BCL-X L , levels have frequently been described as a prominent determinant of primary venetoclax sensitivity in MCL, and, moreover, upregulation of these proteins has been reported as a mechanism of resistance to prolonged venetoclax treatment. 3 The up-regulated MCL-1 and BCL-X L proteins serve as a buffer for the released BH3-only proteins upon venetoclax treatment, resulting in reduced BAK/BAX oligomerization and thus reduced apoptosis ( Figure 8 ). Accordingly, venetoclax combined with MCL-1 inhibitors demonstrated strong synergy in several pre-clinical MCL models (Figure 5D; Online Supplementary Figure S6B ).…”

“…Accordingly, venetoclax combined with MCL-1 inhibitors demonstrated strong synergy in several pre-clinical MCL models (Figure 5D; Online Supplementary Figure S6B ). 3 , 16 , 17 However, in vivo toxicities such as cardiotoxicity have thus far hampered the development and clinical approval of MCL-1 therapy. 3 Indirect inhibition of MCL-1 by targeting a tumor-specific molecule such as CK2 might prevent these toxicities, especially since silmitasertib showed a safe tolerability profile in clinical trials (NCT03904862, NCT03897036, NCT03571438, NCT04668209, NCT04663737).…”

“… 2 For malignant transformation, additional aberrations are required, including alterations in the mitochondrial apoptotic pathway, such as upregulation of BCL-2, BCL-X L and Bcl-W and deletion of BIM. 3 Hence, targeting anti-apoptotic BCL-2 family proteins is an attractive option for the treatment of MCL.…”