Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation.
Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation.
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DOI：
10.1158/2159-8290.cd-20-1863
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发表时间：
2021-12-01
期刊：
影响因子：
28.2
通讯作者：
Sen, Triparna
中科院分区：
文献类型：
--
作者：
Quintanal-Villalonga, Alvaro;Taniguchi, Hirokazu;Zhan, Yingqian A.;Hasan, Maysun M.;Chavan, Shweta S.;Meng, Fanli;Uddin, Fathema;Manoj, Parvathy;Donoghue, Mark T. A.;Won, Helen H.;Chan, Joseph M.;Ciampricotti, Metamia;Chow, Andrew;Offin, Michael;Chang, Jason C.;Ray-Kirton, Jordana;Tischfield, Sam E.;Egger, Jacklynn, V;Bhanot, Umesh K.;Linkov, Irina;Asher, Marina;Sinha, Sonali;Silber, Joachim;Iacobuzio-Donahue, Christine A.;Roehrl, Michael H.;Hollmann, Travis J.;Yu, Helena A.;Qiu, Juan;de Stanchina, Elisa;Baine, Marina K.;Rekhtman, Natasha;Poirier, John T.;Loomis, Brian;Koche, Richard P.;Rudin, Charles M.;Sen, Triparna
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。由于缺乏转化前/转化后的临床样本，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 肿瘤的详细基因组、表观基因组、转录组和蛋白质特征以及转化前/转化后样品支持 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 通路的药理学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神经内分泌转化的潜在驱动因素和治疗脆弱性的新景观。
Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUADs) 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-/post-transformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre-/post-transformation samples, support 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 PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacological 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 neuroendocrine transformation in lung cancer.