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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC

Qin Shen1,2, Chen Mei1,2,3, Yidan Chen4

  • 1MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.

The EMBO Journal
|July 10, 2026
PubMed

Insights

Mutant EGFR in non-small cell lung cancer hijacks the cGAS-STING-TBK1 pathway for survival and resistance. Disrupting this innate immune signaling sensitizes tumors to chemotherapy, revealing a new therapeutic vulnerability.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Epidermal growth factor receptor (EGFR) mutations drive non-small cell lung cancer (NSCLC).
  • Therapeutic resistance to third-generation tyrosine kinase inhibitors (TKIs) is a significant clinical hurdle in NSCLC.
  • The mechanisms underlying TKI resistance remain incompletely understood.

Purpose of the Study:

  • To investigate a novel tumor cell-intrinsic mechanism of EGFR-driven NSCLC resistance.
  • To explore the role of innate immune signaling pathways in sustaining oncogenic signaling and therapeutic resistance.
  • To identify potential therapeutic strategies targeting this newly discovered pathway.

Main Methods:

  • Investigated the interaction between mutant EGFR (mEGFR) and the cGAS-STING-TBK1 innate immune pathway.
  • Utilized genetic and pharmacological approaches to disrupt mEGFR-STING-TBK1 signaling.
  • Assessed therapeutic efficacy in patient-derived NSCLC organoids and immunocompetent murine models.

Main Results:

  • Mutant EGFR aberrantly associates with STING, phosphorylates STING and TBK1, leading to TBK1 stabilization and hyperactivation.
  • This interaction establishes a kinase loop crucial for DNA damage repair, contributing to therapeutic resistance.
  • Disruption of mEGFR-STING-TBK1 coupling sensitized resistant NSCLC organoids to chemotherapy.
  • Combined TBK1 inhibition and cisplatin suppressed mEGFR-driven tumors in preclinical models.

Conclusions:

  • Mutant EGFR exploits the cGAS-STING-TBK1 pathway for oncogenic signaling and therapeutic resistance in NSCLC.
  • The cGAS-STING pathway plays a role in DNA damage tolerance, paradoxically utilized by oncogenic mutations.
  • Targeting the mEGFR-STING-TBK1 axis represents a promising therapeutic vulnerability for NSCLC treatment.

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