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<p>EGFR hotspot mutations (mEGFR), including primary L858R, exon 19 deletion, and secondary T790M, are pivotal oncogenic drivers in human non-small cell lung cancer (NSCLC). At the same time, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized tumor cell-intrinsic mechanism in which mutant EGFR (mEGFR) exploits innate immune signaling via the cGAS–STING–TBK1 pathway to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly associates with STING signalosomes and phosphorylates STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 and establishing an unexpected kinase loop critical for DNA damage repair. Genetic or pharmacological disruption of mEGFR–STING–TBK1 coupling sensitizes resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin suppressed mEGFR-driven tumors in murine models of spontaneous and immunocompetent NSCLC and in patient-derived organoids. Our findings suggest a new function of cGAS–STING in DNA damage tolerance, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.</p>

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Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Qin Shen,
  • Chen Mei,
  • Yidan Chen,
  • Qian Zhang,
  • Qingzhe Wu,
  • Xinyuan Yu,
  • Fei Zhang,
  • Shengduo Liu,
  • Chen Chen,
  • Cunqi Ye,
  • Qi Zhang,
  • Xin-Hua Feng,
  • Li Shen,
  • Hai Song,
  • Tingbo Liang,
  • Penghong Song,
  • Bing Xia,
  • Pinglong Xu

摘要

EGFR hotspot mutations (mEGFR), including primary L858R, exon 19 deletion, and secondary T790M, are pivotal oncogenic drivers in human non-small cell lung cancer (NSCLC). At the same time, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized tumor cell-intrinsic mechanism in which mutant EGFR (mEGFR) exploits innate immune signaling via the cGAS–STING–TBK1 pathway to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly associates with STING signalosomes and phosphorylates STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 and establishing an unexpected kinase loop critical for DNA damage repair. Genetic or pharmacological disruption of mEGFR–STING–TBK1 coupling sensitizes resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin suppressed mEGFR-driven tumors in murine models of spontaneous and immunocompetent NSCLC and in patient-derived organoids. Our findings suggest a new function of cGAS–STING in DNA damage tolerance, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.