Open AccessEGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer
Author(s) -
Ke Gong,
Gao Guo,
Nishah Panchani,
Matthew E. Bender,
David E. Gerber,
John D. Minna,
Farjana J. Fattah,
Boning Gao,
Michael Peyton,
Kemp H. 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
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0048-0
Subject(s) - cancer research , ubiquitin ligase , erlotinib , lung cancer , kras , downregulation and upregulation , egfr inhibitors , signal transduction , epidermal growth factor receptor , medicine , ubiquitin , cancer , chemistry , biology , microbiology and biotechnology , biochemistry , colorectal cancer , gene
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 IFN-I upregulation via a RIG-I-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 interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-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 NSCLC patients.