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Cancer Discov. 2019 Jan;9(1):34-45. doi: 10.1158/2159-8290.CD-18-0689. Epub 2018 Oct 8.

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy.
5
University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia.
6
Department of Human Genetics, Graduate School of Biomedical Science, Tokushima University, Tokushima, Japan.
7
Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
8
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
9
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
10
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
11
MCB Department, Brown University, Providence, Rhode Island.
12
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. dbarbie@partners.org.

Abstract

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.See related commentary by Corte and Byers, p. 16.This article is highlighted in the In This Issue feature, p. 1.

PMID:
30297358
PMCID:
PMC6328329
[Available on 2020-01-01]
DOI:
10.1158/2159-8290.CD-18-0689

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