EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer
| Autor: | David E. Gerber, Esra A. Akbay, Farjana J. Fattah, Kathryn H. Dao, Bipasha Mukherjee, Chao Xing, Amyn A. Habib, Boning Gao, Shanrong Zhang, Matthew E. Bender, Kemp H. Kernstine, Cheng Ming Chiang, Ke Gong, John D. Minna, Gao Guo, Michael Peyton, Dawen Zhao, Nishah Panchani, Adwait Amod Sathe, Sandeep Burma |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Lung Neoplasms medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Downregulation and upregulation TANK-binding kinase 1 Carcinoma Non-Small-Cell Lung Animals Humans Medicine Lung cancer Protein Kinase Inhibitors neoplasms Cell Proliferation biology business.industry Wild type medicine.disease respiratory tract diseases Ubiquitin ligase ErbB Receptors Oncology 030220 oncology & carcinogenesis biology.protein Cancer research KRAS Signal transduction business Signal Transduction |
| Zdroj: | Nature Cancer. 1:394-409 |
| ISSN: | 2662-1347 |
| DOI: | 10.1038/s43018-020-0048-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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