Abstract
Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax.
Highlights
The Bcl-2 protein family regulates the onset of apoptosis by critically controlling mitochondrial outer membrane permeabilization [1,2]
We found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva venetoclax-resistant Riva (VR), while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL
Ever since its launch in the clinic, venetoclax has been a precision medicine with great potential and success [11]. While initially it was approved as a therapy for chronic lymphocytic leukemia (CLL), current research focuses on its use in other types of cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, myeloma and acute myeloid leukemia [11,14,15]
Summary
The Bcl-2 protein family regulates the onset of apoptosis by critically controlling mitochondrial outer membrane permeabilization [1,2]. Anti-apoptotic Bcl-2 protein family members are upregulated in various cancers, e.g., chronic lymphocytic leukemia (CLL) [4], diffuse large B-cell lymphoma (DLBCL) [4], and solid tumors such as prostate cancer [5] This enables cancer cells to survive despite pro-apoptotic, oncogenic stress [6]. Venetoclax is the first clinically used BH3 mimetic to treat relapsed CLL cancer patients [8,9,10] and does so by occupying the hydrophobic groove of the anti-apoptotic protein Bcl-2 [7,11] This prevents the sequestration of pro-apoptotic Bcl-2 family proteins, often upregulated due to oncogenic stress [12] and tips cancer cells “addicted” to Bcl-2 for survival over the edge of apoptosis [13]. While initially it was approved as a therapy for CLL, current research focuses on its use in other types of cancer such as DLBCL, follicular lymphoma, myeloma and acute myeloid leukemia [11,14,15]
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