Small cell lung cancer (SCLC) represents ∼15% of all lung cancer diagnoses in the US and has a particularly poor prognosis. We hypothesized that kinases regulating SCLC survival pathways represent therapeutically targetable vulnerabilities whose inhibition may improve SCLC outcome. A shRNA library targeting all human kinases was introduced into seven chemonaive patient derived xenografts (PDX), and cells cultured in vitro and in vivo. On harvest, lost, or depleted, shRNAs were considered as regulating cell survival pathways, and deemed essential kinases. Unsupervised hierarchical cluster analysis of recovered shRNAs separated the PDX into two clusters suggesting kinase based heterogeneity among the SCLC PDX. Twenty-three kinases were identified as essential in two or more PDX, with mTOR a candidate essential kinase in four. mTOR phosphorylation (p-mTOR) status correlated with PDX sensitivity to mTOR kinase inhibition, and mTOR inhibition sensitized PDX to cisplatin/etoposide. In PDX where mTOR was defined as essential, mTOR inhibition caused a 43% decrease in tumor volume at 21 days (P<0.01). Combining mTOR inhibition with cisplatin/etoposide decreased PDX tumor volume 96% compared to cisplatin/etoposide alone at 70 days (P<0.002). Chemoresistance did not develop with the combination of mTOR inhibition and cisplatin/etoposide in mTOR essential PDX over 105 days. The prevalence of p-mTOR in a tissue microarray of chemonaive SCLC was 27% identifying a significant SCLC subtype that might benefit by the addition of mTOR inhibition to standard chemotherapy. These studies show that kinases can define SCLC subgroups, can identify therapeutic vulnerabilities, and can potentially be used to optimize therapeutic approaches.

中文翻译：

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mTOR 作为 SCLC 中必需激酶的作用

小细胞肺癌 (SCLC) 占美国所有肺癌诊断的 15%，预后特别差。我们假设调节 SCLC 生存途径的激酶代表治疗上可靶向的脆弱性，其抑制可能会改善 SCLC 的结果。将靶向所有人类激酶的 shRNA 文库引入到 7 个未接受化学治疗的患者衍生异种移植物 (PDX) 以及体外和体内培养的细胞中。在收获、丢失或耗尽时，shRNA 被认为是调节细胞存活途径，并被认为是必需的激酶。回收的 shRNA 的无监督层次聚类分析将 PDX 分成两个簇，表明 SCLC PDX 中基于激酶的异质性。23 种激酶在两种或多种 PDX 中被确定为必需激酶，其中 mTOR 是四种中的候选必需激酶。mTOR 磷酸化 (p-mTOR) 状态与 PDX 对 mTOR 激酶抑制的敏感性相关，mTOR 抑制使 PDX 对顺铂/依托泊苷敏感。在 mTOR 被定义为必需的 PDX 中，mTOR 抑制导致 21 天肿瘤体积减少 43%（P<0.01）。与单独使用顺铂/依托泊苷相比，mTOR 抑制与顺铂/依托泊苷在 70 天时可减少 96% 的 PDX 肿瘤体积（P<0.002）。在 105 天内 mTOR 必需 PDX 中 mTOR 抑制和顺铂/依托泊苷的组合没有产生化学抗性。p-mTOR 在化学初治 SCLC 组织微阵列中的流行率为 27%，确定了一种重要的 SCLC 亚型，该亚型可能因在标准化疗中添加 mTOR 抑制而受益。这些研究表明，激酶可以定义 SCLC 亚组，可以识别治疗漏洞，