期刊
CANCER DISCOVERY
卷 9, 期 1, 页码 34-45出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-0689
关键词
-
类别
资金
- Gloria T. Maheu, Heerwagen, Candice Bagby, and Gross-Loh Family Funds for Lung Cancer Research
- JSPS Postdoctoral Fellowship for Research Abroad
- Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]
- American Association for Cancer Research, the Scientific Partner of SU2C
- [NCI-R01 CA190394-02]
- [NIH-U01 CA2143A1-01]
- NATIONAL CANCER INSTITUTE [P01CA154303, U01CA214381, R01CA190394] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM126043] Funding Source: NIH RePORTER
KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)-mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. SIGNIFICANCE: Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据