Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.

中文翻译：

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蛋白磷酸酶 2A 作为小细胞肺癌的治疗靶点


蛋白磷酸酶 2A (PP2A) 是一种丝氨酸/苏氨酸磷酸酶，参与细胞凋亡、增殖和 DNA 损伤反应的调节，在许多癌症中过度表达，包括小细胞肺癌 (SCLC)。在此，我们报道了 LB100（一种 PP2A 小分子抑制剂）与铂类化疗联合使用时，在体外和体内协同引发抗肿瘤反应，且无明显毒性。使用电感耦合等离子体质谱法，我们定量确定了 LB100 的致敏作用是通过 SCLC 细胞中卡铂的摄取增加介导的。单独或联合使用 LB100 治疗会抑制 SCLC 二维培养物和三维球体模型中的细胞活力，减少葡萄糖摄取，并减弱线粒体和糖酵解 ATP 的产生。 LB100 与 atezolizumab 组合可增加 T 细胞浸润和杀死肿瘤球体的能力，而 LB100 与卡铂组合可引起 DNA 修复标记物 γH2AX 过度磷酸化并增强细胞凋亡，同时减弱 MET 信号传导和通过内皮细胞单层的侵袭。总而言之，这些数据凸显了 LB100 抑制 PP2A 联合铂类化疗和免疫疗法在 SCLC 中的转化潜力。