Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia.
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res. 2021 Apr 15;81(8):2056-2070. doi: 10.1158/0008-5472.CAN-20-1756. Epub 2021 Feb 11.
Oncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain-containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphorylation and expression in glioblastoma cells across 40 signaling pathway nodes in response to different drugs and for different oxygen tensions revealed that SHP2 antagonism has network-level, context-dependent signaling consequences that affect cell phenotypes (e.g., cell death) in unanticipated ways. To map specific signaling consequences of SHP2 antagonism to phenotypes of interest, a data-driven computational model was constructed based on the paired signaling and phenotype data. Model predictions aided in identifying three signaling processes with implications for treating glioblastoma with SHP2 inhibitors. These included PTEN-dependent DNA damage repair in response to SHP2 inhibition, AKT-mediated bypass resistance in response to chronic SHP2 inhibition, and SHP2 control of hypoxia-inducible factor expression through multiple MAPKs. Model-generated hypotheses were validated in multiple glioblastoma cell lines, in mouse tumor xenografts, and through analysis of The Cancer Genome Atlas data. Collectively, these results suggest that in glioblastoma, SHP2 inhibitors antagonize some signaling processes more effectively than existing kinase inhibitors but can also limit the efficacy of other drugs when used in combination. SIGNIFICANCE: These findings demonstrate that allosteric SHP2 inhibitors have multivariate and context-dependent effects in glioblastoma that may make them useful components of some combination therapies, but not others.
致癌蛋白酪氨酸磷酸酶一直被视为有吸引力的药物靶点，最近开发的含 SH2 结构域的磷酸酶-2（SHP2）别构抑制剂已进入临床试验。然而，磷酸酶调节许多直接或间接的靶点，以及促进和拮抗致癌信号的能力，可能使磷酸酶抑制的疗效难以预测。在这里，我们研究了拮抗 SHP2 在胶质母细胞瘤中的后果，SHP2 已被提议作为一种有用的药物靶点，在这种难治性癌症中。测量 40 个信号通路节点中不同药物和不同氧张力下胶质母细胞瘤细胞的蛋白磷酸化和表达，揭示了 SHP2 拮抗具有网络级、上下文相关的信号后果，以意想不到的方式影响细胞表型（例如，细胞死亡）。为了将 SHP2 拮抗的特定信号后果映射到感兴趣的表型，我们基于配对的信号和表型数据构建了一个数据驱动的计算模型。模型预测有助于确定与 SHP2 抑制剂治疗胶质母细胞瘤相关的三种信号过程。其中包括 SHP2 抑制后 PTEN 依赖性的 DNA 损伤修复、慢性 SHP2 抑制后的 AKT 介导的旁路耐药，以及 SHP2 通过多种 MAPK 对缺氧诱导因子表达的控制。在多个胶质母细胞瘤细胞系、小鼠肿瘤异种移植和对癌症基因组图谱数据的分析中验证了模型生成的假设。总的来说，这些结果表明，在胶质母细胞瘤中，SHP2 抑制剂比现有的激酶抑制剂更有效地拮抗一些信号过程，但在联合使用时也可能限制其他药物的疗效。
这些发现表明，在胶质母细胞瘤中，别构 SHP2 抑制剂具有多变量和上下文相关的作用，这可能使它们成为某些联合治疗方案的有用组成部分，但不是其他方案。
