Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.
单药维奈托克/ABT-199（抗凋亡蛋白BCL2抑制剂）的临床试验表明，弥漫性大B细胞淋巴瘤（DLBCL）的生存并非仅依赖BCL2。深入探究增强维奈托克敏感性的通路/蛋白或维奈托克耐药DLBCL的特异性脆弱点，将为治疗提供新的潜在途径。为此，我们构建了获得性维奈托克耐药DLBCL细胞系，并与固有耐药及敏感DLBCL细胞系进行对比研究。研究发现，固有耐药与获得性耐药存在不同的BCL2家族成员改变，并增强了对特定通路的依赖性。虽然联合使用BCL2家族抑制剂可能克服维奈托克耐药，但RNA测序及药物/化合物筛选显示，维奈托克耐药DLBCL细胞（包括TP53突变型）对氧化磷酸化存在优先依赖性。抑制线粒体电子传递链复合物I可诱导维奈托克耐药（而非敏感）DLBCL细胞死亡。抑制线粒体氧化还原调节因子IDH2能协同克服维奈托克耐药。此外，获得性与固有耐药DLBCL细胞对转录抑制剂、B细胞受体信号通路抑制剂及I类组蛋白去乙酰化酶抑制剂具有相似敏感性。这些方法在DLBCL、滤泡性淋巴瘤和边缘区淋巴瘤患者样本中同样有效。本研究揭示了多种规避或克服DLBCL及其他B细胞淋巴瘤中维奈托克耐药机制的途径，并为未来临床研究确定了关键的可靶向通路。
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