PXD079783

PXD079783 is an original dataset announced via ProteomeXchange.

Title	On-target toxicity limits the efficacy of CDK11 inhibition against cancers with 1p36 deletions
Description	The cyclin-dependent kinase CDK11 is an understudied kinase that has been the subject of conflicting reports regarding its function in cancer. Here, we combine genetic and pharmacological approaches to demonstrate that CDK11 is a critical regulator of cancer cell survival that is required for RNA splicing and the expression of homologous recombination genes. Inhibition of CDK11 disrupts genome stability, promotes the retention of intronic sequences in mature mRNAs, and induces synthetic lethality with PARP inhibitors. Through integrative analysis of functional genomics datasets, we identify heterozygous deletions of chromosome 1p36 - which encompasses CDK11 and its activating cyclin CCNL2 - as a recurrent and predictive biomarker of sensitivity to CDK11 inhibition. To assess the therapeutic potential of CDK11, we develop MEL-495R, a selective and orally bioavailable CDK11 inhibitor. Additionally, we establish a genetically-engineered mouse model that allows us to differentiate between the on-target and off-target effects of CDK11 inhibitors in vivo. Using this platform, we demonstrate that MEL-495R induces widespread on-target toxicity, revealing a narrow therapeutic index. Together, these findings define CDK11 as a core cancer dependency, uncover a chromosomal deletion that sensitizes tumors to CDK11 inhibition, and provide a generalizable strategy for deconvolving drug efficacy and toxicity in vivo for novel oncology targets.
HostingRepository	PRIDE
AnnounceDate	2026-08-07
AnnouncementXML	Submission_2026-08-07_11:54:21.890.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD079783
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Lu Qiao
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2026-06-16 17:08:44	ID requested
⏵ 1	2026-08-07 11:54:22	announced

Julian L, Crozier L, Lukow D, Mishra S, Swamy A, Hagenson RA, Sennhenn P, Sausville EL, Mendelson B, Chuaqui C, Qiao L, Vasudevan A, Lin KT, Bhatia S, Bertomeu T, Chatr-Aryamontri A, Zhang L, Rees MG, Ronan MM, Roth JA, Nottoli T, Bai S, Lakshmipathi J, Muthusamy V, Van Vranken JG, Gygi SP, Thompson SL, Smith JC, Anderson K, Shah S, Bindra RS, Akerman M, Spector DL, Krainer AR, Sheltzer JM, On-target toxicity limits the efficacy of CDK11 inhibition against cancers with 1p36 deletions. bioRxiv, ():(2025) [pubmed]

10.6019/PXD079783;

10.1101/2025.08.03.668359;

submitter keyword: kinase inhibitor, OTS964, splicing,CDK11, cell cycle

Jason Sheltzer
contact affiliation	Stanford Cancer Institute, Stanford University
contact email	sheltzer@stanford.edu
lab head
Lu Qiao
contact affiliation	Stanford University
contact email	luqiao@stanford.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/2026/08/PXD079783

PRIDE project URI

• PRIDE
  1. PXD079783
     1. Label: PRIDE project
     2. Name: On-target toxicity limits the efficacy of CDK11 inhibition against cancers with 1p36 deletions