PXD052290-1

PXD052290 is an original dataset announced via ProteomeXchange.

Title	NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors
Description	Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status
HostingRepository	PRIDE
AnnounceDate	2025-12-15
AnnouncementXML	Submission_2025-12-14_16:15:31.632.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Antrix Jain
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-16 05:18:27	ID requested
⏵ 1	2025-12-14 16:15:32	announced

10.1126/scitranslmed.adq5492;

Zheng ZY, Chen A, Jaehnig EJ, Anurag M, Lei JT, Feng L, Wang C, Fandino D, Singh P, Kennedy H, Yadav G, Vollert CT, Tsai J, Chen X, Li Y, Lim B, Thompson A, Li S, Foulds CE, Zhang B, Ellis MJ, Chang EC, breast cancers are differentially sensitive to CDK4/6 inhibitors. Sci Transl Med, 17(813):eadq5492(2025) [pubmed]

submitter keyword: NF1, neurofibromin 1, CDK4, RAF,breast cancer, estrogen receptor

Eric C Chang
contact affiliation	Breast Center, Baylor College of Medicine, Houston, TX US
contact email	echang1@bcm.edu
lab head
Antrix Jain
contact affiliation	Baylor College of Medicine
contact email	antrixj@bcm.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD052290

PRIDE project URI

• PRIDE
  1. PXD052290
     1. Label: PRIDE project
     2. Name: NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors