PXD055112-1

PXD055112 is an original dataset announced via ProteomeXchange.

Title	Targeting G1–S Checkpoint–Compromised Cancers with Cyclin A/B RxL Inhibitors
Description	Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.
HostingRepository	PRIDE
AnnounceDate	2025-05-30
AnnouncementXML	Submission_2025-05-30_02:03:29.283.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-23 00:48:40	ID requested
⏵ 1	2025-05-30 02:03:29	announced

Dataset with its publication pending

submitter keyword: macrocycle,Cyclin A, E2F, Cyclin B, Cy/RxL motif, CDK2, SAC, synthetic lethality

Matthew G Oser
contact affiliation	, Dana-Farber Cancer Institute, Harvard Medical School 360 Longwood Avenue Longwood Center, LC4117 Boston, MA 02215
contact email	matthew_oser@dfci.harvard.edu
lab head
iolanda Vendrell
contact affiliation	Target Discovery Institute, NDMRB
contact email	iolanda.vendrell@ndm.ox.ac.uk
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/2025/05/PXD055112

PRIDE project URI

• PRIDE
  1. PXD055112
     1. Label: PRIDE project
     2. Name: Targeting G1–S Checkpoint–Compromised Cancers with Cyclin A/B RxL Inhibitors