EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer

Ke Gong, Gao Guo, Nishah Panchani, Matthew E. Bender, David E. Gerber, John D. Minna, Farjana Fattah, Boning Gao, Michael Peyton, Kemp Kernstine, Bipasha Mukherjee, Sandeep Burma, Cheng Ming Chiang, Shanrong Zhang, Adwait Amod Sathe, Chao Xing, Kathryn H. Dao, Dawen Zhao, Esra A. Akbay, Amyn A. Habib

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild-type (EGFRwt) tumors. Here we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers type I interferon (IFN)-I upregulation via a RIG-I–TANK-binding kinase 1 (TBK1)–IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates IFNs via a NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-tyrosine kinase inhibitor (TKI) sensitivity in EGFR-mutant NSCLC and renders EGFRwt/KRAS-mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR-TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR-TKI plus IFN-neutralizing antibody could be useful in most patients with NSCLC.

Original languageEnglish (US)
Pages (from-to)394-409
Number of pages16
JournalNature Cancer
Volume1
Issue number4
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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