Systems biology approaches can identify critical targets in complex cancer signaling networks to inform therapy combinations and overcome conventional treatment resistance. Herein, we developed a data-driven, network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Integrated analysis of 1,046 childhood B-ALL cases identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Consistent with network controllability theory, combination small molecule inhibitor therapy targeting a pair of key nodes shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Functional validation experiments further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple patient-derived xenograft models. Our study represents a broadly-applicable conceptual framework for combinatorial drug discovery, based on systematic interrogation of synergistic vulnerability pathways with pharmacologic targeted validation in sophisticated preclinical human leukemia models.

中文翻译：

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网络分析揭示了费城染色体样急性淋巴细胞白血病中合理组合治疗的协同遗传依赖性。

系统生物学方法可以识别复杂的癌症信号网络中的关键靶标，从而为治疗组合提供信息并克服传统的治疗阻力。本文中，我们开发了一种基于数据驱动，基于网络可控制性的方法，以鉴定费城染色体样B急性淋巴细胞白血病（Ph样B-ALL）中的协同关键调节靶标，Phase B急性淋巴细胞白血病是一种与高信号转导相关的高危白血病亚型和化学抗性。对1,046例儿童B-ALL病例的综合分析确定了Ph样ALL中14个失调的网络结点，这些结节参与了异常的JAK / STAT，Ras / MAPK和凋亡通路以及其他关键过程。与网络可控性理论一致，针对一对关键节点的联合小分子抑制剂疗法使Ph样ALL细胞的转录组状态转变为不太像激酶激活的BCR-ABL1重排（Ph +）B-ALL，而更类似于对预后有利的儿童B-ALL亚型。功能验证实验进一步证明了在人Ph样ALL细胞系中体外和在多个患者衍生异种移植模型中体内结合使用BCL-2抑制剂Venetoclax和酪氨酸激酶抑制剂ruxolitinib或dasatinib增强的抗白血病功效。我们的研究代表了组合药物发现的广泛适用的概念框架，该框架基于在复杂的临床前人类白血病模型中以药理学靶向验证对协同脆弱性途径进行系统性询问。