BFL-1 expression determines the efficacy of venetoclax in MYC+/BCL2+ double hit lymphoma

Esteve-Arenys, Anna; Roué, Gaël

doi:10.18632/oncoscience.402

Cited by 7 publications

(10 citation statements)

References 8 publications

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“…Previous reports also revealed a high expression of MCL1 in venetoclaxresistant cells, which is similar to that found in HL60/VEN cells. Esteve-Arenys et al (31,32) reported that the accumulation of BCL2-related protein A1 is a major mechanism involved in acquired resistance to venetoclax; findings of the present study were comparable with this. Recently, Haselager et al (33) demonstrated that BCL2-like 1 (BCL2L1) was also important in venetoclax resistance in chronic lymphocytic leukemia cells; however, the mRNA expression of BCL2L1 was found to be comparable between HL60 and HL60/VEN cells in this study (Figure 2A).…”

Section: Discussionsupporting

confidence: 89%

Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells

et al. 2021

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Background/Aim: Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs. Materials and Methods: Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells. Results: HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax. Conclusion: HL60/VEN cells exhibited upregulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.Venetoclax is a first-in-class, oral, selective inhibitor of BCL2 apoptosis regulator (BCL2) that is approved worldwide (1, 2). Venetoclax as monotherapy or in combination with rituximab is an effective treatment, provides durable responses in adults with recurrent/refractory chronic lymphocytic leukemia, and has a manageable safety profile in pivotal clinical trials (3-5). Trials are currently underway to expand its use for various other types of cancer, including multiple myeloma and chronic myeloid leukemia (6, 7).BCL2 an anti-apoptotic protein is a regulator of cell death (i.e., apoptosis) (8). Evasion of apoptosis is one of the typical characteristics of cancer cells, and a change in expression of BCL2 family proteins has been reported in many cancer types (9-11). Therefore, current interest is focused on targeting BCL2 to treat various hematological malignancies, which are typically mediated by the intrinsic regulation of apoptosis or dysregulation of the mitochondrial pathway (12-14). Venetoclax binds and neutralizes BCL2 (BH3 domain), resulting in the release of cytochrome c from the mitochondria and subsequent activation of the intrinsic apoptotic pathway through a caspase cleavage cascade (8,15,16).Multidrug resistance remains a significant problem in cancer chemotherapy (17,18). Tumor cells have been found to acquire resistance not only to cytotoxic anticancer drugs, but also to molecular targeting agents. To date, the mechanisms of resistance to venetoclax have been investigated, and changes in molecular profiles have been found to occur in venetoclax-resistant cells (19). Although resistance to venetoclax is regarded as a clinical problem (20, 21), it is unclear whether resistance to venetoclax induces resistance to drugs besides venetoclax i.e., leads to cross-resistance.

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Section: Discussionsupporting

confidence: 89%

Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells

et al. 2021

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“…Similarly, it was found that Bfl‐1 conferred resistance to CLL cells treated with ABT737 (the earlier Bcl‐2/Bcl‐xL antagonist, recently replaced by the FDA‐approved Bcl‐2‐selective Venetoclax/ABT199) (Al‐Harbi et al, ; Yecies, Carlson, Deng, & Letai, ). More recent studies identified Bfl‐1 to be overexpressed in lymphoma, both in cell lines and in primary cultures, after prolonged exposure to Venetoclax, confirming the role of Bfl‐1 in acquired resistance to Bcl‐2 antagonists (Esteve‐Arenys & Roue, ). Likewise, we and others found that Bfl‐1 is highly expressed in melanomas (Placzek et al, ), where its overexpression could be associated with resistance to chemotherapy and to the BRAF inhibitor vemurafenib (Hind et al, ).…”

Section: Discussionmentioning

confidence: 69%

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

et al. 2020

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Recently, it was reported that tetrapeptides cyclized via lactam bond between the amino terminus and a glutamic residue in position 4 (termed here N‐lock) can nucleate helix formation in longer peptides. We applied such strategy to derive N‐locked covalent BH3 peptides that were designed to selectively target the anti‐apoptotic protein Bfl‐1. The resulting agents were soluble in aqueous buffer and displayed a remarkable (low nanomolar) affinity for Bfl‐1 and cellular activity. The crystal structure of the complex between such N‐locked covalent peptide and Bfl‐1 provided insights on the geometry of the N‐locking strategy and of the covalent bond between the agent and Bfl‐1.

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“…Combined, the BH3 mimetic and Bim interaction studies allow us to establish a hierarchy of Bcl-2 members in binding to Bim: Bcl-2>Bcl-XL>Mcl-1>Bfl-1, when all four are present. When all available BH3 mimetics were applied, Bim interacted with Bfl-1, confirming that Bfl-1 can also bind Bim in primary leukemic cells and thus potentially could play a role in venetoclax resistance in CLL 2,44 .…”

Section: Discussionmentioning

confidence: 78%

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

Haselager

Kielbassa

Burg

et al. 2020

Blood

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Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Since ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment combined with dissecting functional interactions of Bcl-2 family members in an in vitro model for venetoclax resistance. In the PB, recent LN emigrants had higher Bcl-XL and Mcl-1 expression than cells immigrating back to the LN. Under ibrutinib treatment, this distinction collapsed, and significantly, the pre-treatment profile reappeared in patients who relapsed on ibrutinib. In response to venetoclax however, Bcl-2 members displayed an early increase, underlining the different modes of action of these two drugs. Profiling by BH3 mimetics was performed in CLL cells fully resistant to venetoclax due to CD40-mediated induction of Bcl-XL, Mcl-1 and Bfl-1. Several dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL cells. Lastly, we demonstrated that pro-apoptotic Bim interacts with anti-apoptotic Bcl-2 members in a sequential manner: Bcl-2>Bcl-XL>Mcl-1>Bfl-1. Combined, the data indicate that Bcl-XL is more important in venetoclax resistance than Mcl-1 and provide biological rationale for potential synergy between ibrutinib and venetoclax.

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BFL-1 expression determines the efficacy of venetoclax in MYC+/BCL2+ double hit lymphoma

Cited by 7 publications

References 8 publications

Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells

Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

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