Evidence map›Paper›PMID 40091835›Full record

ArticleThe Journal of clinical investigation2025

Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS-mutant cancer models.

Shihui Shen, Qiansen Zhang, Yuhan Wang, Hui Chen, Shuangming Gong, Yun Liu, Conghao Gai, Hansen Chen, Enhao Zhu, Bo Yang and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

24 authors.

Shihui ShenShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Qiansen ZhangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Yuhan WangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Hui ChenJoint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, China.
Shuangming GongShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Yun LiuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Conghao GaiOrganic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, China.
Hansen ChenShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Enhao ZhuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Bo YangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Lin LiuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Siyuan CaoShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Mengting ZhaoShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Wenjie RenShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Mengjuan LiShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Zhuoya PengShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Lu ZhangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Shaoying ZhangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Juwen ShenShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Bianhong ZhangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Patrick Kh LeeSchool of Energy and Environment, City University of Hong Kong, Hong Kong SAR, China.
Kun LiHealth Science Center, East China Normal University, Shanghai, China.
Lei LiJoint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, China.
Huaiyu YangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REGγ as a mutant KRAS-associated factor that enhanced REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a REGγ-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REGγ-proteasome by increasing REGγ expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS-mutant cancers.

Indexed as

AutoantigensDrug Resistance, NeoplasmNeoplasmsProteasome Endopeptidase ComplexProteasome InhibitorsProto-Oncogene Proteins p21(ras)AdultAgedAged, 80 and overAnimalsAntineoplastic Combined Chemotherapy ProtocolsCell LineFemaleGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsAutoantigensImmune Checkpoint InhibitorsKi antigenNF-E2-Related Factor 2Pancreatitis-Associated ProteinsPiperazinesProteasome Endopeptidase ComplexProteasome InhibitorsProto-Oncogene Proteins p21(ras)PyridinesPyrimidinesREG3G protein, humansotorasibUbiquitinCancerDrug therapyOncologyTherapeuticsTumor suppressors

Identifiers

PMID40091835
PMCPMC11910216

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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.