EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer
- 6 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (4), 394-409
- https://doi.org/10.1038/s43018-020-0048-0
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.Keywords
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