Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations

蛋白质基因组学 癌症研究 克里唑蒂尼 转录组 STK11段 克拉斯 阿波贝克 肺癌 医学 DNA甲基化 生物 基因 遗传学 突变 内科学 基因组 基因表达 恶性胸腔积液
作者
Seung‐Jin Park,Shinyeong Ju,Sung‐Ho Goh,Byoung-Ha Yoon,Jong‐Lyul Park,Jeong‐Hwan Kim,Seonjeong Lee,Sang-Jin Lee,Yumi Kwon,Wonyeop Lee,Kyung Chan Park,Geon Kook Lee,Seog Yun Park,Sunshin Kim,Seon‐Young Kim,Ji‐Youn Han,Cheolju Lee
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (9): 1491-1503
标识
DOI:10.1158/0008-5472.can-23-1551
摘要

Abstract Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. Significance: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.
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