a Department of Molecular, Cellular, and Developmental Biology , University of Colorado Boulder , Boulder , CO , USA.
b Department of Pharmacology and Toxicology , University of Alabama , Birmingham , AL , USA.
Cell Cycle. 2018;17(11):1329-1344. doi: 10.1080/15384101.2018.1480224. Epub 2018 Jul 23.
The tumor suppressor protein p53 is central to the cellular stress response and may be a predictive biomarker for cancer treatments. Upon stress, wildtype p53 accumulates in the nucleus where it enforces cellular responses, including cell cycle arrest and cell death. p53 is so dominant in its effects, that p53 enforcement - or - restoration therapy is being studied for anti-cancer therapy. Two mechanistically distinct small molecules that act via p53 are the selective inhibitor of nuclear export, selinexor, and MDM2 inhibitor, nutlin-3a. Here, individual cells are studied to define cell cycle response signatures, which captures the variability of responses and includes the impact of loss of p53 expression on cell fates. The individual responses are then used to build the population level response. Matched cell lines with and without p53 expression indicate that while loss-of-function results in altered cell cycle signatures to selinexor treatment, it does not diminish overall cell loss. On the contrary, response to single-agent nutlin-3a shows a strong p53-dependence. Upon treatment with both selinexor and nutlin-3a there are combination effects in at least some cell lines - even when p53 is absent. Collectively, the findings indicate that p53 does act downstream of selinexor and nutlin-3a, and that p53 expression is dispensable for selinexor to cause cell death, but nutlin-3a response is more p53-dependent. Thus, TP53 disruption and lack of expression may not predict poor cell response to selinexor, and selinexor's mechanism of action potentially provides for strong efficacy regardless of p53 function.
抑癌蛋白 p53 是细胞应激反应的核心，可能是癌症治疗的预测性生物标志物。在应激状态下，野生型 p53 在细胞核中积累，从而强制细胞产生反应，包括细胞周期停滞和细胞死亡。p53 的作用非常显著，因此正在研究 p53 强制执行或恢复治疗作为抗癌疗法。两种通过 p53 起作用的机制不同的小分子是核输出选择性抑制剂 selinexor 和 MDM2 抑制剂 nutlin-3a。在这里，研究单个细胞以定义细胞周期反应特征，该特征捕获了反应的可变性，并且包括 p53 表达缺失对细胞命运的影响。然后，将个体反应用于构建群体水平反应。具有和不具有 p53 表达的匹配细胞系表明，虽然功能丧失会导致 selinexor 治疗的细胞周期特征发生改变，但不会减少总体细胞丢失。相反，单独使用 nutlin-3a 的反应表现出强烈的 p53 依赖性。在用 selinexor 和 nutlin-3a 治疗时，至少在一些细胞系中存在联合作用 - 即使没有 p53。总的来说，这些发现表明 p53 确实作用于 selinexor 和 nutlin-3a 的下游，并且 p53 表达对于 selinexor 引起细胞死亡是可有可无的，但 nutlin-3a 的反应更依赖于 p53。因此，TP53 缺失和表达缺失可能不能预测细胞对 selinexor 的反应不佳，并且 selinexor 的作用机制可能提供了强大的疗效，而与 p53 功能无关。
