Oncogenic EGFR rewires STING-TBK1 immune machinery by tyrosine phosphorylation to license DNA damage tolerance

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Shen Qin  

LAB HEAD: Pinglong Xu

PROVIDER: PXD074679 | Pride | 2026-07-01

REPOSITORIES: Pride