Evidence map›Paper›PMID 31874110›Full record

ArticleThe Journal of clinical investigation2020

Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma.

Kewen Hu, Kun Li, Jing Lv, Jie Feng, Jing Chen, Haigang Wu, Feixiong Cheng, Wenhao Jiang, Jieqiong Wang, Haixiang Pei and 5 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 269 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
269citing papers in PubMed, 1 pooled it
20.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

269 citing papers in PubMed, 1 synthesis or guideline pooled it, 384 citations in OpenAlex.

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209 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 7 institutions in 2 countries.

Kewen HuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Kun LiShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Jing LvShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Jie FengBeijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Jing ChenKey Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, China.
Haigang WuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Feixiong ChengGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Wenhao JiangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Jieqiong WangCancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Haixiang PeiShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Paul J ChiaoDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Zhenyu CaiNational Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Yihua ChenShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Mingyao LiuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Xiufeng PangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
East China Normal University · CNFudan University Shanghai Cancer Center · CNCapital Medical University · CNCleveland Clinic Lerner College of Medicine · USNingxia Medical University · CNSecond Military Medical University · CNThe University of Texas MD Anderson Cancer Center · US

Funding

The molecular mechanisms of metabolism reprogramming in mutant Kras/Ink4a-driven pancreatic ductal adenocarcinomaR01CA207031 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI CHIAO, PAUL J · 2017 to 2021
$1.8M
NCI NIH HHS R01 CA207031
6 · The paper itself

Abstract

Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.

Indexed as

Adenocarcinoma of LungAmino Acid Transport System y+MutationProto-Oncogene Proteins p21(ras)A549 CellsAnimalsAntineoplastic AgentsApoptosisEndoplasmic Reticulum StressGlutathioneHumansLung NeoplasmsMiceMice, Inbred BALB CMice, NudeXenograft Model Antitumor AssaysAmino Acid Transport System y+Antineoplastic AgentsGlutathioneKRAS protein, humanProto-Oncogene Proteins p21(ras)SLC7A11 protein, humanCancerDrug therapyOncology

Identifiers

PMID31874110
PMCPMC7108883
OpenAlexW2998103954

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.