Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer. Significance: The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung. See related commentary by Meador and Lovly, [p. 2962][1] . This article is highlighted in the In This Issue feature, [p. 2945][2] [1]: /lookup/volpage/11/2962?iss=12 [2]: /lookup/volpage/11/2945?iss=12

中文翻译：

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肺肿瘤的多组学分析定义了神经内分泌转化中激活的途径

谱系可塑性与多种癌症的治疗耐药性有关。在适合靶向治疗的肺腺癌（LUAD）中，转化为小细胞肺癌（SCLC）是一种公认​​的耐药机制。由于转化前/转化后临床样本的缺乏，定义肺癌神经内分泌（NE）转化的分子机制受到限制。联合 LUAD/SCLC 肿瘤以及转化前/转化后样品的详细基因组、表观基因组、转录组和蛋白质表征支持 NE 转化主要由转录重编程而非突变事件驱动。我们确定了有利于 NE 转化的基因组背景，包括 3p 染色体臂的频繁丢失。我们观察到 PRC2 复合体、PI3K/AKT 和 NOTCH 通路相关基因的表达增强。在 EGFR 突变患者来源的异种移植模型中，PI3K/AKT 通路的药物抑制可延迟肿瘤生长和 NE 转化。我们的研究结果定义了肺癌 NE 转化的潜在驱动因素和治疗脆弱性的新景观。意义：转化样本收集的困难阻碍了分子分析的进行，因此对导致 LUAD 向 SCLC 转化的谱系可塑性机制知之甚少。在这里，我们描述了转化时失调的生物途径，并确定了肺中 NE 转化的潜在预测因素和潜在治疗脆弱性。参见 Meador 和 Lovly 的相关评论，[p. 11]。2962][1]。本文在本期专题中突出显示，[p. 11]。2945][2] [1]: /lookup/volpage/11/2962?iss=12 [2]: /lookup/volpage/11/2945?iss=12