PXD059364

PXD059364 is an original dataset announced via ProteomeXchange.

Title	Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS mutant cancers
Description	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 enhances REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a novel mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a novel 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.
HostingRepository	iProX
AnnounceDate	2025-01-01
AnnouncementXML	Submission_2025-10-30_17:37:03.779.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shihui Shen
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-01 21:07:58	ID requested
⏵ 1	2025-10-30 17:37:04	announced

Shen S, Zhang Q, Wang Y, Chen H, Gong S, Liu Y, Gai C, Chen H, Zhu E, Yang B, Liu L, Cao S, Zhao M, Ren W, Li M, Peng Z, Zhang L, Zhang S, Shen J, Zhang B, Lee PK, Li K, Li L, Yang H, Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS-mutant cancer models. J Clin Invest, 135(6):(2025) [pubmed]

submitter keyword: pan-KRAS mutant cancers, the ubiquitin-independent proteasome inhibition, therapeutic target, NRF2, REGγ-proteasome, small molecule inhibitor, drug resistance

Lei Li
contact affiliation	East China Normal University
contact email	lli@bio.ecnu.edu.cn
lab head
Shihui Shen
contact affiliation	East China Normal University
contact email	shshen@bio.ecnu.edu.cn
dataset submitter

iProX dataset URI