Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 85% of all lung cancers are non–small cell histology [non–small cell lung cancer (NSCLC)]. Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than 15% of patients survive beyond 5 years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells, which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive IFN-stimulated gene expression, including an IFN-related DNA damage resistance signature, predicts for sensitivity to SAR. Importantly, tumor cell–intrinsic expression of PD-L1 is IFN-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition. Mol Cancer Ther; 17(4); 732–9. ©2018 AACR.

中文翻译：

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JAK2 抑制剂 SAR302503 消除 PD-L1 表达并靶向治疗耐药的非小细胞肺癌

肺癌是全球癌症相关死亡的主要原因。大约 85% 的肺癌属于非小细胞组织学 [非小细胞肺癌 (NSCLC)]。NSCLC靶向驱动癌基因和免疫检查点的现代治疗策略。然而，只有不到 15% 的患者存活超过 5 年。在这里，我们研究了选择性 JAK2 抑制剂 SAR302503 (SAR) 对 NSCLC 细胞系和肿瘤的影响。我们表明 SAR 对 NSCLC 细胞具有细胞毒性，这些细胞对基因毒性疗法（例如电离辐射、顺铂和依托泊苷）具有抗性。我们证明了组成型 IFN 刺激的基因表达，包括与 IFN 相关的 DNA 损伤抗性特征，可以预测对 SAR 的敏感性。重要的是，PD-L1 的肿瘤细胞内在表达是 IFN 诱导的，并被 SAR 消除。综合起来，这些发现表明 JAK2 抑制剂具有潜在的双重作用，既可以作为对基因毒性治疗耐药的 NSCLC 的新型单一疗法，也可以与免疫检查点抑制结合使用。摩尔癌症治疗；17（4）；732-9。©2018 AACR。