T cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10–15% of childhood and 20–25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL. We treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models. All NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups. We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control. These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.

中文翻译：

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PSEN1 选择性 γ-分泌酶抑制联合激酶或 XPO-1 抑制剂有效靶向 T 细胞急性淋巴细胞白血病

T 细胞急性淋巴细胞白血病 (T-ALL) 是一种高危亚型，占儿童 ALL 病例的 10-15% 和成人 ALL 病例的 20-25%。超过 70% 的 T-ALL 患者在 NOTCH1 信号通路中存在激活突变，并且预计对γ-分泌酶抑制剂敏感。我们最近证明选择性抑制含有 PSEN1 的 γ-分泌酶复合物可以克服与广泛的 γ-分泌酶抑制剂相关的剂量限制性毒性。在这项研究中，我们开发了与 PSEN1 选择性γ-分泌酶抑制剂 MRK-560 和其他靶向药物（激酶抑制剂鲁索替尼和伊马替尼；XPO-1 抑制剂 KPT-8602/eltanexor）的联合治疗策略，用于治疗 T-ALL。我们单独使用 MRK-560 或与其他靶向抑制剂（鲁索替尼、伊马替尼或 KPT-8602/eltanexor）联合治疗了体外 T-ALL 细胞系和体内 T-ALL 患者来源的异种移植 (PDX) 模型。我们确定了对 PDX 模型中细胞系增殖和白血病发展和存活的影响。所有 NOTCH1 信号依赖性 T-ALL 细胞系都对 MRK-560 敏感，并且它与 JAK1 或 ABL1 依赖性细胞系中的鲁索替尼或伊马替尼联合可协同抑制白血病增殖。我们还在所有 NOTCH1 依赖性 T-ALL 细胞系中观察到 MRK-560 和 KPT-8602（eltanexor）之间的强协同作用。在具有 NOTCH1 或 FBXW7 突变的各种 T-ALL PDX 模型中也观察到了这种协同作用。与单一治疗组相比，联合治疗显着减少了体内白血病浸润，并带来了生存益处。与对照相比，我们没有观察到单一药物或联合治疗的小鼠体重减轻或杯状细胞增生。这些数据表明，通过添加其他靶向抑制剂，可以协同增强 PSEN1 选择性 γ-分泌酶抑制的抗白血病作用。MRK-560 与 KPT-8602 的组合是一种高效的治疗组合，它避免了鉴定额外突变的需要，并在体内提供了明显的生存益处。这些有希望的临床前数据保证了基于 PSEN1 选择性γ-分泌酶抑制的 T-ALL 联合治疗策略的进一步开发。