| First Author | Gong K | Year | 2020 |
| Journal | Nat Cancer | Volume | 1 |
| Issue | 4 | Pages | 394-409 |
| PubMed ID | 33269343 | Mgi Jnum | J:304433 |
| Mgi Id | MGI:6508489 | Doi | 10.1038/s43018-020-0048-0 |
| Citation | Gong K, et al. (2020) EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer. Nat Cancer 1(4):394-409 |
| abstractText | 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-kappaB-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. |
