PXD071473

PXD071473 is an original dataset announced via ProteomeXchange.

Title	CDK12 regulates protein translation independent of kinase activity and its degradation sensitizes colorectal cancer to mTOR inhibition
Description	Despite advances in treatment, colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, with limited therapeutic options for patients at advanced or metastatic stage. Synthetic lethality represents an emerging strategy that can expand options for patients unresponsive to existing therapies. However, characterizing effective synthetic lethal gene pairs remains a challenge. In this study, we used comprehensive bioinformatics approaches to identify that CDK12 and mTOR are synthetically lethal in CRC and propose a potential drug combination strategy. We demonstrate that the CDK12 degrader BSJ-4-116 and the mTOR inhibitor everolimus synergistically inhibit CRC cell proliferation and induce apoptosis, both in vitro and in vivo. Notably, this synergistic effect is independent of CDK12’s kinase activity and arises from the blockage of protein synthesis. Mechanistically, CDK12 promotes rRNA 2’-O-methylation, ribosome biogenesis, and protein translation by orchestrating the morphology and function of FBL and NPM1. The combined deficiency of CDK12 and mTOR inhibition synergistically remodels the translatome, affecting key oncogenic drivers such as KRAS and MDM2. Importantly, this combination therapy inhibited tumor growth in patient-derived xenografts, highlighting its potential clinical relevance. Our study uncovers a novel, kinase-independent function of CDK12 in protein translation and elucidates the synergistic benefits of CDK12 degraders and mTOR inhibitors, offering a promising new therapeutic strategy for colorectal cancer.
HostingRepository	PRIDE
AnnounceDate	2026-03-19
AnnouncementXML	Submission_2026-03-18_18:27:29.544.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kailin Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-02 08:51:01	ID requested
⏵ 1	2026-03-18 18:27:30	announced

Dataset with its publication pending

submitter keyword: Human,colorectal cancer,interaction,CDK12

Kailin Li
contact affiliation	Zhejiang University
contact email	12019017@zju.edu.cn
lab head
Kailin Li
contact affiliation	Zhejiang University
contact email	12019017@zju.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071473
     1. Label: PRIDE project
     2. Name: CDK12 regulates protein translation independent of kinase activity and its degradation sensitizes colorectal cancer to mTOR inhibition