Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
Cancer Res. 2021 Dec 1;81(23):6029-6043. doi: 10.1158/0008-5472.CAN-21-1023. Epub 2021 Oct 8.
The family of PIM serine/threonine kinases includes three highly conserved oncogenes, and , which regulate multiple prosurvival pathways and cooperate with other oncogenes such as . Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including . Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab , increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
PIM 丝氨酸/苏氨酸激酶家族包括三个高度保守的癌基因 、 和 ，它们调节多种生存促进途径，并与其他癌基因（如 ）合作。最近的基因组 CRISPR-Cas9 筛选进一步强调了 PIM 在弥漫性大 B 细胞淋巴瘤（DLBCL）细胞中的致癌功能，这证明了小分子 PIM 抑制剂的开发和 PIM 激酶在淋巴瘤中的治疗靶向是合理的。然而，PIM 抑制在 DLBCL 中的详细后果仍未定义。使用化学和遗传 PIM 阻断，我们全面描述了 PIM 激酶相关的生存促进功能在 DLBCL 中的作用，以及 PIM 抑制诱导毒性的机制。在临床开发中使用泛 PIM 抑制剂 SEL24/MEN1703 处理 DLBCL 细胞，可降低 BAD 磷酸化和帽依赖性蛋白翻译，降低 MCL1 表达，并诱导细胞凋亡。PIM 激酶与诊断性 DLBCL 活检中的 MYC 紧密共表达，在细胞系和患者来源的原发性淋巴瘤细胞中抑制 PIM 会降低 MYC 水平以及多个 MYC 依赖性基因的表达，包括 。化学和遗传 PIM 抑制以 MYC 依赖的方式上调表面 CD20 水平。一致地，MEN1703 和其他临床可用的泛 PIM 抑制剂与抗 CD20 单克隆抗体利妥昔单抗协同作用 ，增加补体依赖性细胞毒性和抗体介导的吞噬作用。与 PIM 抑制剂和利妥昔单抗联合治疗比单独使用任何一种药物更有效地抑制淋巴瘤异种移植物的肿瘤生长。综上所述，这些结果表明，DLBCL 中的 PIM 靶向具有多种作用，包括直接细胞毒性和增强对抗 CD20 抗体的敏感性，这证明了这种组合策略的进一步临床开发是合理的。意义：这些发现表明，抑制 PIM 通过 MYC 依赖性和非依赖性机制诱导 DLBCL 细胞死亡，并通过增加 CD20 表达增强对抗 CD20 抗体的治疗反应。
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