TBK1 promotes DNA damage repair
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.