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Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.
Park, Seung-Jin; Ju, Shinyeong; Goh, Sung-Ho; Yoon, Byoung-Ha; Park, Jong-Lyul; Kim, Jeong-Hwan; Lee, Seonjeong; Lee, Sang-Jin; Kwon, Yumi; Lee, Wonyeop; Park, Kyung Chan; Lee, Geon Kook; Park, Seog Yun; Kim, Sunshin; Kim, Seon-Young; Han, Ji-Youn; Lee, Cheolju.
Afiliação
  • Park SJ; Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Ju S; Department of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea.
  • Goh SH; Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
  • Yoon BH; National Cancer Center, Goyang, Republic of Korea.
  • Park JL; Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Kim JH; Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Lee S; Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Lee SJ; Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Kwon Y; Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
  • Lee W; Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea.
  • Park KC; National Cancer Center, Goyang, Republic of Korea.
  • Lee GK; Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
  • Park SY; National Cancer Center, Goyang, Republic of Korea.
  • Kim S; Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Kim SY; Department of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea.
  • Han JY; National Cancer Center, Goyang, Republic of Korea.
  • Lee C; National Cancer Center, Goyang, Republic of Korea.
Cancer Res ; 84(9): 1491-1503, 2024 May 02.
Article em En | MEDLINE | ID: mdl-38607364
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Estrogênios / Receptores ErbB / Proteogenômica / Adenocarcinoma de Pulmão / Quinase do Linfoma Anaplásico / Neoplasias Pulmonares / Mutação Limite: Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Estrogênios / Receptores ErbB / Proteogenômica / Adenocarcinoma de Pulmão / Quinase do Linfoma Anaplásico / Neoplasias Pulmonares / Mutação Limite: Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article