EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
entrez:
3
12
2020
pubmed:
4
12
2020
medline:
4
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33269343
doi: 10.1038/s43018-020-0048-0
pmc: PMC7706867
mid: NIHMS1637068
pii: 10.1038/s43018-020-0048-0
doi:
Substances chimiques
Protein Kinase Inhibitors
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
394-409Subventions
Organisme : NIH HHS
ID : S10 OD023552
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244212
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197796
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176284
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194578
Pays : United States
Organisme : BLRD VA
ID : I01 BX002559
Pays : United States
Commentaires et corrections
Type : CommentIn
Déclaration de conflit d'intérêts
Competing Interests Statement The authors declare no competing interests.
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