PXD074679-1

PXD074679 is an original dataset announced via ProteomeXchange.

Title	Oncogenic EGFR rewires STING-TBK1 immune machinery by tyrosine phosphorylation to license DNA damage tolerance
Description	EGFR hotspot mutations (mEGFR), including primary drivers such as L858R and exon 19 deletions, and the frequently acquired resistance mutation T790M, are pivotal oncogenic drivers in non-small cell lung cancer (NSCLC). Yet, resistance to third-generation tyrosine kinase inhibitors (TKIs) remains unresolved. Here, we uncover a previously unrecognized immunological mechanism whereby mEGFR (such as L858R/T790M and delE746-A750) exploit cGAS-STING innate immune signaling, conventionally regarded as tumor-suppressive, to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly incorporates into STING signalosomes, directly phosphorylating STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing activated TBK1 proteins and establishing an unexpected and self-sustaining kinase loop critical for DNA damage repair and chemoresistance. Disruption of this mEGFR-STING-TBK1 axis, genetically or pharmacologically, profoundly sensitized resistant NSCLC cells and patient-derived organoids to chemotherapy. Combining TBK1 inhibition with cisplatin notably eradicated mEGFR-driven tumors in spontaneous and immunocompetent NSCLC models and patient-derived organoids. Our findings redefine cGAS-STING signaling within the tumor-immune interplay, revealing its paradoxical exploitation by primary oncogenic mutations and, thereby, unveiling a novel innate immune checkpoint and therapeutic vulnerability in NSCLC.
HostingRepository	PRIDE
AnnounceDate	2026-07-01
AnnouncementXML	Submission_2026-07-01_07:01:48.802.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shen Qin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-20 03:26:29	ID requested
⏵ 1	2026-07-01 07:01:49	announced

Dataset with its publication pending

submitter keyword: tyrosine phosphorylation, Chemoresistance, cGAS-STING, EGFR-TKIs,EGFR, TBK1

Pinglong Xu
contact affiliation	Zhejiang University
contact email	Xupl@zju.edu.cn
lab head
Shen Qin
contact affiliation	ZheJiang University
contact email	shenqin@zju.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074679
     1. Label: PRIDE project
     2. Name: Oncogenic EGFR rewires STING-TBK1 immune machinery by tyrosine phosphorylation to license DNA damage tolerance