EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer

Gong, Ke; Guo, Gao; Panchani, Nishah; Bender, Matthew E.; Gerber, David E.; Minna, John D.; Fattah, Farjana; Gao, Boning; Peyton, Michael; Kernstine, Kemp; Mukherjee, Bipasha; Burma, Sandeep; Chiang, Cheng-Ming; Zhang, Shanrong; Amod Sathe, Adwait; Xing, Chao; Dao, Kathryn H.; Zhao, Dawen; Akbay, Esra A.; Habib, Amyn A.

doi:10.1038/s43018-020-0048-0

Cited by 92Lung Cancer Treatments and Mutationsinterferon and immune responsesHER2/EGFR in Cancer Research

EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer

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Gong, Ke, Guo, Gao, Panchani, Nishah, Bender, Matthew E., Gerber, David E., Minna, John D., Fattah, Farjana, Gao, Boning +12 more·2020·Nature Cancer

DOI 10.1038/s43018-020-0048-0PMC PMC7706867

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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 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.

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EGFR inhibition in lung cancer triggers an adaptive response by co-opting interferon antiviral signaling pathways.
“Finally, a recent study by Gong et al. reported that EGFR inhibition in lung cancer triggers an adaptive response by co-opting interferon antiviral signaling pathways [115].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [115]

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MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I
Brägelmann, J., Lorenz, C., Borchmann, S., Nishii, K., Wegner, J., Meder, L., Ostendorp, J., Ast, D., Heimsoeth, A., Nakasuka, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25728-8 · Cited by 75 · see citing works
Role of K63-linked ubiquitination in cancer
Cao, L., Liu, X., Zheng, B., Xing, C., & Liu, J. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01204-0 · Cited by 73 · see citing works
“In addition, TRIM32 is responsible for K63-linked ubiquitination and activation of TBK1 upon EGFR suppression, which exerts efficacy in treating non-small cell lung cancer [229].”
Background
TP53 gain-of-function mutations promote osimertinib resistance via TNF-α–NF-κB signaling in EGFR-mutated lung cancer
Ibusuki, R., Iwama, E., Shimauchi, A., Tsutsumi, H., Yoneshima, Y., Tanaka, K., & Okamoto, I. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00557-2 · Cited by 47 · see citing works
“Although gene ampli ﬁ cation of MET or HER2 and transformation to small cell lung cancer have been identi ﬁ ed in osimertinib-resistant tumors 5 – 8 , and cytokinessuchastumornecrosisfactor-α (TNF-α )andinterferonhavebeen associated with the development of EGFR-TKI resistance in NSCLC 9,10 , the .”
MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer
Yoshida, R., Saigí, M., Tani, T., Springer, B. F., Shibata, H., Kitajima, S., Mahadevan, N. R., Campisi, M., Kim, W., Kobayashi, Y., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0770 · Cited by 47 · see citing works
“org Cancer Res; 82(21) November 1, 2022 4081”
BackgroundInfluential
EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation
Guo, G., Gong, K., Beckley, N. A., Zhang, Y., Yang, X., Chkheidze, R., Hatanpaa, K. J., Garzón-Muvdi, T., Koduru, P. R. K., Nayab, A., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00962-4 · Cited by 45 · see citing works
A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
Gurule, N. J., McCoach, C. E., Hinz, T. K., Merrick, D. T., Bokhoven, A. V., Kim, J., Patil, T., Calhoun, J., Nemenoff, R. A., Tan, A. C., et al. (2021) · npj Precision Oncology · doi:10.1038/s41698-021-00181-4 · Cited by 39 · see citing works
Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer
Cai, X., Jing, M., Sun, R., Wang, S., Molina‐Vila, M. Á., CHAIB-OUKADOUR, I., Rosell, R., & Cao, P. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105701 · Cited by 41 · see citing works
Cancer Cell-Specific Major Histocompatibility Complex II Expression as a Determinant of the Immune Infiltrate Organization and Function in the NSCLC Tumor Microenvironment
Johnson, A. M., Boland, J. M., Wrobel, J., Kleczko, E. K., Weiser-Evans, M. C. M., Hopp, K., Heasley, L. E., Clambey, E. T., Jordan, K. R., Nemenoff, R. A., et al. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.05.004 · Cited by 40 · see citing works
Cell-Intrinsic Mechanisms of Drug Tolerance to Systemic Therapies in Cancer
Léonce, C., Saintigny, P., & Ortiz‐Cuaran, S. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0038 · Cited by 37 · see citing works
Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments
Chen, S., Tang, J., Liu, F., Li, W., Yan, T., Shangguan, D., Yang, N., & Liao, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1094764 · Cited by 31 · see citing works
“Moreover, the upregulation of type I IFN was triggered via a RIG-I-TBK1-IRF3 pathway in EGFR-MT cells (104).”
Background
Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer
Liu, Y., Crowe, W. N., Wang, L., Petty, W. J., Habib, A. A., & Zhao, D. (2022) · Nano Research · doi:10.1007/s12274-022-5205-6 · Cited by 31 · see citing works
Cancer cell-autonomous cGAS-STING response confers drug resistance
Lv, Q.-M., Lei, H.-M., Wang, S., Zhang, K., Tang, Y., Shen, Y. H., Lu, L., Chen, H., & Zhu, L. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.05.005 · Cited by 30 · see citing works
EGFR inhibition in EGFR ‐mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment
Shiiya, A., Noguchi, T., Tomaru, U., Ariga, S., Takashima, Y., Ohhara, Y., Taguchi, J., Takeuchi, S., Shimizu, Y., Kinoshita, I., et al. (2022) · Cancer Science · doi:10.1111/cas.15701 · Cited by 19 · see citing works
Characteristics and molecular mechanism of drug-tolerant cells in cancer: a review
Liang, X.-W., Liu, B., Chen, J.-C., Cao, Z. W., Chu, F.-R., Xiong, L., Wang, S.-Z., & Wu, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1177466 · Cited by 20 · see citing works
EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy
Gu, Y., He, H., Qiao, S., Shao, Y., Wang, L., Zhang, Z., Zhang, L., & Zhou, F. (2025) · Advanced Science · doi:10.1002/advs.202505785 · Cited by 17 · see citing works
Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction
Zhao, X., Liu, B., William, W. N., Tsanov, K. M., Ho, Y.-J., Barriga, F. M., Lim, R. J., Trifas, M., Khandekar, A., Du, Y., et al. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.12.020 · Cited by 17 · see citing works
A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine
Sattler, M., Mambetsariev, I., Fricke, J., Tan, T., Liu, S., Vaidehi, N., Pisick, E. P., Mirzapoiazova, T., Rock, A., Merla, A., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12051936 · Cited by 16 · see citing works
“Even though not defined in EGF inhibitor resistance models, the activation of signal transduction and activator of transcription 3 (STAT3) [62], the RIG-I-TBK1-IRF3 axis [63] or nuclear factor-κB (NF-κB) [64] may induce residual signaling during the inhibition of EGFR in dependent cells that could be sufficient for th…”
Background
Human cytomegalovirus UL23 exploits PD-L1 inhibitory signaling pathway to evade T cell-mediated cytotoxicity
Yuan, Q., Fan, Z., Huang, W., Huo, X., Yang, X., Ran, Y., Chen, J., & Li, H. (2024) · mBio · doi:10.1128/mbio.01191-24 · Cited by 16 · see citing works
Anti-galectin-9 therapy synergizes with EGFR inhibition to reprogram the tumor microenvironment and overcome immune evasion
Linghu, D., Song, J., Gu, L., Liu, C., Liu, B., Yang, R., Chen, Q., Yao, J., Manickam, S. P., Sundhar, N., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010926 · Cited by 15 · see citing works
IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non–small cell lung cancer
Ibusuki, R., Iwama, E., Shimauchi, A., Kawano, H., Mizusaki, S., Nakamura, S., Miyazaki, Y., Inutsuka, Y., Hashisako, M., Harada, T., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02493-6 · Cited by 16 · see citing works
Modulating environmental signals to reveal mechanisms and vulnerabilities of cancer persisters
Sun, X., Bieber, J. M., Hammerlindl, H., Chalkley, R. J., Li, K. H., Burlingame, A. L., Jacobson, M. P., Wu, L. F., & Altschuler, S. J. (2022) · Science Advances · doi:10.1126/sciadv.abi7711 · Cited by 15 · see citing works
“This was motivated by recent observations that STAT1 expression can be increased by various cancer drugs ( 20 , 21 , 32 ).”
PD-L1 and PD-L2 immune checkpoint protein induction by type III interferon in non-small cell lung cancer cells
Larsen, T. V., Daugaard, T. F., Gad, H. H., Hartmann, R., & Nielsen, A. L. (2023) · Immunobiology · doi:10.1016/j.imbio.2023.152389 · Cited by 15 · see citing works
PIKfyve, expressed by CD11c-positive cells, controls tumor immunity
Choi, J. E., Qiao, Y., Kryczek, I., Yu, J., Gurkan, J. K., Bao, Y., Gondal, M. N., Tien, J. C.-Y., Maj, T., Yazdani, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48931-9 · Cited by 14 · see citing works
“More recently, preclinical studies have included characterization of the immunesystem,focusingonassociationsbetweentreatmentresponse andTcellpro ﬁ les 29 – 34 .”
Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids
Gong, K., Guo, G., Beckley, N. A., Yang, X., Zhang, Y., Gerber, D. E., Minna, J. D., Burma, S., Zhao, D., Akbay, E. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27276-7 · Cited by 15 · see citing works
Targeting mutant EGFR in non-small cell lung cancer in the context of cell adaptation and resistance
Roberts, S. K., Galgadas, I., Clarke, D. T., Zanetti-Domingues, L. C., Gervasio, F. L., & Martin-Fernandez, M. L. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104407 · Cited by 14 · see citing works
RETRACTED ARTICLE: AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell cycle-regulated U2AF2 RNA splicing
Laliotis, G. I., Chavdoula, E., Paraskevopoulou, M., Kaba, A., Ferlita, A. L., Singh, S., Anastas, V., Nair, K. A., Orlacchio, A., Taraslia, V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24795-1 · Cited by 12 · see citing works
Retracted
JAC4 Inhibits EGFR-Driven Lung Adenocarcinoma Growth and Metastasis through CTBP1-Mediated JWA/AMPK/NEDD4L/EGFR Axis
Ding, K., Jiang, X., Wang, Z., Zou, L., Cui, J., Li, X., Shu, C., Li, A., & Zhou, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108794 · Cited by 12 · see citing works
“In addition to the inevitable acquired resistance, a large number of NSCLC patients harboring wild-type (WT) EGFR do not respond to TKIs despite EGFR overexpression [14].”
Background
RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32
Wang, L., Song, Y., Wang, Y., Liu, X.-X., Yin, Y.-L., Gao, S., Zhang, F., Li, L., & Zhang, Z. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106995 · Cited by 11 · see citing works
Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations
Thomas, B. J., Awan, S. Z., Joshi, T., Daniëls, M. A., Porciani, D., & Burke, D. H. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00758-9 · Cited by 11 · see citing works
The Role of Amino Acid Metabolic Reprogramming in Tumor Development and Immunotherapy
Khan, S. U., & Khan, M. U. (2022) · Biochemistry and Molecular Biology · doi:10.11648/j.bmb.20220701.12 · Cited by 11 · see citing works
“Correspondingly, EGFR antitumor drugs can activate the interferon pathway, leading to drug resistance of tumor cells [17].”
Background
Inhibition of TRIM32 by ibr‐7 treatment sensitizes pancreatic cancer cells to gemcitabine via mTOR/p70S6K pathway
Zhang, B., Yan, Y., Gu, Y., Teng, F., Xu, L., Zhou, X., Che, J., Dong, X., Zhou, L., & Lin, N. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17109 · Cited by 11 · see citing works
Targeting oncogenic signal pathway to improve cancer immunotherapy: Insights and perspectives
Yang, Q., Sun, H., & Sun, Z. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117043 · Cited by 10 · see citing works
MicroRNAs and Drug Resistance in Non-Small Cell Lung Cancer: Where Are We Now and Where Are We Going
Cuttano, R., Afanga, M. K., & Bianchi, F. (2022) · Cancers · doi:10.3390/cancers14235731 · Cited by 10 · see citing works
The efficacy and safety of immune checkpoint inhibitors for patients with EGFR ‐mutated non‐small cell lung cancer who progressed on EGFR tyrosine‐kinase inhibitor therapy: A systematic review and network meta‐analysis
Wang, Z., Zhou, F., Xu, S., Wang, K., & Ding, H. (2023) · Cancer Medicine · doi:10.1002/cam4.6453 · Cited by 10 · see citing works
“49,50 Changes in TME can also be detected after acquiring EGFR-TKI resistance in NSCLC. Peng et al. found that c-MET amplification and hepatocyte growth factor (HGF) can activate PI3K/Akt, MAPK, and other signaling pathways, and HGF can also regulate the proliferation of T lymphocytes and the…”
Background
Retinoic acid-inducible gene-I like receptor pathway in cancer: modification and treatment
Du, G., Xing, Z., Zhou, J., Cui, C., Liu, C., Liu, Y., & Li, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1227041 · Cited by 10 · see citing works
“Loss of RIG-I enhances the sensitivity of EGFR mutant cells to erlotinib in NSCLC (82).”
BackgroundInfluential
Novel systemic therapies in the management of tyrosine kinase inhibitor-pretreated patients with epidermal growth factor receptor-mutant non-small-cell lung cancer
Li, Y.-S., Jie, G., & Wu, Y.-L. L. C. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359231193726 · Cited by 10 · see citing works
Multiomic Profiling Identified EGF Receptor Signaling as a Potential Inhibitor of Type I Interferon Response in Models of Oncolytic Therapy by Vesicular Stomatitis Virus
Nikitina, A. S., Lipatova, A. V., Goncharov, A. O., Kliuchnikova, A. A., Pyatnitskiy, M. A., Kuznetsova, K. G., Hamad, A., Vorobyev, P. O., Alekseeva, O. N., Mahmoud, M., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095244 · Cited by 10 · see citing works
“These experiments showed that gefitinib and its analogs act through endogenous interferon production, as described earlier [32], and through the cross-talk it t e i terferon signaling [30].”
BackgroundMethodInfluential
Serum cytokine levels and other associated factors as possible immunotherapeutic targets and prognostic indicators for lung cancer
Zhao, Y., Jia, S., Zhang, K., & Zhang, L. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1064616 · Cited by 12 · see citing works
“Lung cancer has been found to have high levels of the cytokine and its receptors TNFR1 and TNFR2 (93).”
Background
TBK1 is paradoxical in tumor development: a focus on the pathway mediating IFN-I expression
Wang, B., Zhang, F., Wu, X., & Ji, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1433321 · Cited by 9 · see citing works
Dependency of EGFR activation in vanadium-based sensitization to oncolytic virotherapy
Wong, B., Bergeron, A., Alluqmani, N., Maznyi, G., Chen, A., Arulanandam, R., & Diallo, J. (2022) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2022.04.004 · Cited by 8 · see citing works
“By the same token, inhibition of EGFR by genetic or pharmacological means has also been reported to activate the interferon pathway in several contexts.(23,52,53) While sustained virus-induced EGFR signaling is likely in part required for its OV-enhancing effect, it is likely that vanadate requires the modulation of o…”
Background
hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC
Trono, P., Tocci, A., Palermo, B., Carlo, A. D., D’Ambrosio, L., D’Andrea, D., Modugno, F. D., Nicola, F. D., Goeman, F., Corleone, G., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-006913 · Cited by 9 · see citing works
Inhibition of proteinase-activated receptor 2 (PAR2) decreased the malignant progression of lung cancer cells and increased the sensitivity to chemotherapy
Huo, H., Feng, Y., & Tang, Q. (2024) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-023-04630-8 · Cited by 7 · see citing works
“The emergence of drug resistance greatly affects the use of targeted drugs [6–8].”
Background
Comparative study of TNF-α and vitamin D reveals a significant role of TNF-α in NSCLC in an ethnically conserved vitamin D deficient population
Bhat, I. A., Mir, I. R., Malik, G. H., Mir, J. I., Dar, T. A., Nisar, S., Naik, N. A., Sabah, Z. U., & Shah, Z. A. (2022) · Cytokine · doi:10.1016/j.cyto.2022.156039 · Cited by 7 · see citing works
CD73 and Adenosine Receptor Signaling as a Potential Therapeutic Target in EGFR-Mutated NSCLC
Pacheco, J. M., & Schenk, E. L. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.01.1623 · Cited by 7 · see citing works
Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors
Liu, L., Zhang, B., Wu, X., Cheng, G., Han, X., Xin, X., Qin, C., Yang, L., Huo, M., & Yin, L. (2024) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2024.102743 · Cited by 6 · see citing works
EGFR blockade activates interferon
Yoshida, R., & Barbie, D. A. (2020) · Nature Cancer · doi:10.1038/s43018-020-0055-1 · Cited by 6 · see citing works
Neoadjuvant tislelizumab with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-1): a phase 2 clinical trial
Wei, Z., Chen, H., Wang, D., Jiang, Z., Pei, Y., Li, L.-Y., Wang, F., Jin, J., Liu, Z., Chen, F., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63978-y · Cited by 5 · see citing works
“…immunity regulated by aberrant EGFR signaling have focused primarily on EGFR-mutant tumorssuchasnon-small cell lung cancer 25,36 , Gong et al. reported that EGFR-TKIs could also upregulate interferon expression in EGFR-wt human cancer cell lines 37 , potentially strengthening antitumor responses.”
Chemotherapy Should Be Combined With Checkpoint Inhibitors in the Treatment of Patients With Stage IV EGFR-Mutant NSCLC Whose Disease Has Progressed on All Available Tyrosine Kinase Inhibitors
Zhou, F., & Zhou, C. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.07.011 · Cited by 5 · see citing works
Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer
Alonso, S., Chu, K., Granowsky, E., Saraiba-Rabanales, V., Parsons, M. J., Gunasinghe, H. I., Shia, J., Yaeger, R., & Dow, L. E. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.04.009 · Cited by 8 · see citing works
miR-191-5p suppresses PRRSV replication by targeting porcine EGFR to enhance interferon signaling
Pan, Y., Zhang, L., Ma, W., Ibrahim, Y. M., Zhang, W., Wang, M., Wang, X., Xu, Y., Gao, C., Chen, H., et al. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1473504 · Cited by 4 · see citing works
Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés‐Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez‐Martinez, J., & Arrieta, O. G. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05471-6 · Cited by 4 · see citing works
“This lack of correlation between CD155 and PD-L1 may be influenced by oncogenic mutations, since EGFR [24] and ALK [25] impair IFN-y signaling and downregulate PD-L1 expression.”
Background
RETRACTED ARTICLE: Phosphor-IWS1-dependent U2AF2 splicing regulates trafficking of CAR-E-positive intronless gene mRNAs and sensitivity to viral infection
Laliotis, G., Kenney, A. D., Chavdoula, E., Orlacchio, A., Kaba, A., Ferlita, A. L., Anastas, V., Tsatsanis, C., Beane, J. D., Sehgal, L., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02668-z · Cited by 4 · see citing works
Retracted
Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection
Zhang, D., Zhao, Y., You, X., He, S., & Li, E. (2023) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01487-22 · Cited by 5 · see citing works
“It was observed that EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer, whereas the genetic or pharmacological inhibition of Axl restores sensitivity to EGFR inhibition through decreased type I IFN expression (52, 53).”
Background
Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in CRCPreprint
Alonso, S., Chu, K., Parsons, M. J., Granowsky, E., Gunasinghe, H. I., Shia, J., Yaeger, R. D., & Dow, L. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.05.668666 · Cited by 4 · see citing works
Streptococcus mutans -derived extracellular vesicles promote herpes simplex virus infection in oral epithelia
Kim, T.-L., Oh, S. Y., Lee, K. Y., Lee, H., Kwon, T., Kim, J. W., Shin, C.-G., Jang, S., Hong, S., & Choi, S. (2025) · Virulence · doi:10.1080/21505594.2025.2602261 · Cited by 3 · see citing works
“Previous studies have suggested that EGFR activation decreases IFN expression [42–47].”
Respiratory emerging viruses and drug resistance in lung cancer: challenges and new perspectives in treatment
Wu, Q., Li, W., Liu, H., Xue, Y., Huang, K., Pourghadamyari, H., & Liu, Z. (2025) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2025.101383 · Cited by 2 · see citing works
Prospective Observational Study Revealing Early Pulmonary Function Changes Associated With Brigatinib Initiation
Ng, T. L., Johnson, A. M., Nemenoff, R. A., Hsieh, E. W. Y., Osypuk, A. A., van Bokhoven, A., Li, H. Y., Camidge, D. R., & Schenk, E. L. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.11.013 · Cited by 2 · see citing works
Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer
Park, S., Haam, K., Heo, H., Kim, D., Kim, M., Jung, H., Cha, S., Kim, S., & Lee, H. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13738 · Cited by 2 · see citing works
“…3-kinase (PI3K) signaling [15], bypassing of the activation of STAT3 [16], TNF [17], and calcium signaling [15], and activation of additional pathways, such as an antiviral defense pathway via interferons [18] — all of these effects contribute to cell survival and the resistance to drug treatment.”
Inflammatory signaling in targeted therapy resistance: focus on EGFR-targeted treatment
Luo, Z., & Gong, K. (2024) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2024.0327 · Cited by 2 · see citing works
Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models
Guo, Y., Huang, D., Zhou, Y., Ran, M., Zhang, S., & Tam, K. Y. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00235 · Cited by 1 · see citing works
KRAS mutated lung adenocarcinoma responds to pan-ERBB and Aurora kinase inhibitors
Uras, I. Z., Trkulja, M. V., Salama, A. K. A. A., Horvath, J., Asnani, K., Trenk, C., Kubicek, S., Bilban, M., Moll, H. P., & Casanova, E. (2026) · npj Precision Oncology · doi:10.1038/s41698-025-01242-8 · Cited by 1 · see citing works
“Notably, similar to EGFR-selective TKI 40,43,53 , afatinib triggered adaptive phosphorylation of AURK in three cell lines and TBK1 in two (consistent with its role in KRAS mutant cell survival 54 ).”
Targeting the TBK1-p62 condensate axis restores sensitivity to EGFR-TKIs in resistant lung cancer
Song, Y., Shao, C., Zhang, Y., Yang, M., Liu, Y., Chen, S. M., Gao, J., Li, Z., Li, B., Yao, X., et al. (2026) · Protein & Cell · doi:10.1093/procel/pwag043 · Cited by 1 · see citing works
GRHL2-HER3 and E-cadherin mediate EGFR-bypass drug resistance in lung cancer cells
Ito, F., Iwata, W., Adachi, Y., Sesaki, H., & Iijima, M. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1511190 · Cited by 1 · see citing works
“The epidermal growth factor receptor (EGFR), which facilitates cell growth and proliferation, is a primary oncogenic driver of NSCLC (Herbst et al., 2018; Gong et al., 2020; Leiter et al., 2023; Liu et al., 2023).”
JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesisPreprint
Li, Z., Zhou, Y., Jia, K., Yang, Y., Zhang, L., Wang, S., Wang, M., Li, Y., Li, N., Yu, Y., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-410612/v1 · Cited by 1 · see citing works
Location of EGFR exon 20 insertions matters
Cardona, A. F., González‐Cao, M., Arrieta, O. G., & Rosell, R. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.06.002
Data from MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer
Yoshida, R., Saigí, M., Tani, T., Springer, B. F., Shibata, H., Kitajima, S., Mahadevan, N. R., Campisi, M., Kim, W., Kobayashi, Y., et al. (2023) · doi:10.1158/0008-5472.c.6514215.v1
Effects of Methylsulfonylmethane and Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor on Cell Proliferation, Cell Cycle and Anti-Inflammatory Effect in Chicken Intestinal Epithelial Cells with Lipopolysaccharide Challenge
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Cholesterol Regulation in the Treatment of Osimertinib-resistant NSCLC: A Review
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TRIM32 positively regulates c-di-GMP-Induced type I interferon signaling pathway in Listeria monocytogenes infection
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Erlotinib induces 3D genome rearrangements in lung cancer cells activating tumor suppressor genes through FOXA2-bound EpromotersPreprint
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VDR Decrease Enhances the Efficacy of 1,25-Dihydroxyvitamin D3 Inhibiting Gefitinib Resistance by Regulating EGFR/FASN Loop in NSCLC Cells
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“Reducing the expression of EGFR can effectively inhibit the resistance of NSCLC to EGFR tyrosine kinase inhibitors (EGFR-TKIs) by suppressing p-EGFR and the EGFR signaling pathway [17,18].”
Additional file 5 of Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés-Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez-Martinez, J.-M., & Arrieta, O. (2024) · Figshare · doi:10.6084/m9.figshare.27012378
Additional file 3 of Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés-Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez-Martinez, J.-M., & Arrieta, O. (2024) · Figshare · doi:10.6084/m9.figshare.27012372
Additional file 2 of Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés-Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez-Martinez, J.-M., & Arrieta, O. (2024) · Figshare · doi:10.6084/m9.figshare.27012369
Additional file 1 of Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés-Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez-Martinez, J.-M., & Arrieta, O. (2024) · Figshare · doi:10.6084/m9.figshare.27012366
Additional file 4 of Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer
Popa-Navarro, X., Avilés-Salas, A., Hernández‐Pedro, N., Orozco‐Morales, M., Caballé‐Perez, E., Castillo-Ruiz, C., Lucio-Lozada, J., Barrios‐Bernal, P., Hernandez-Martinez, J.-M., & Arrieta, O. (2024) · Figshare · doi:10.6084/m9.figshare.27012375
Tumor Microenvironment–Induced IFITM3 Activates MET–AKT Signaling to Drive Osimertinib Resistance in EGFR-Mutant NSCLC
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WNT inhibition activates interferon stimulated gene expression by alleviating epigenetic repression of endogenous retroviruses
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EGFR INHIBITION PROMOTES ENTEROENDOCRINE CELL DIFFERENTIATION CONTRIBUTING TO TREATMENT-ASSOCIATED DIARRHEAPreprint
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“This is especially relevant given that the persistent TME has been described as immunosuppressive, 80,83,84 while the VACV is known to re-engage the immune system against tumor cells.”
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TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer
Gong, K., Guo, G., Gerber, D. E., Gao, B., Peyton, M., Huang, C., Minna, J. D., Hatanpaa, K. J., Kernstine, K., Cai, L., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96148 · Cited by 98 · see citing works
EGFR inhibition in EGFR ‐mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment
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Abstract 3125: IL-6 contributes to the suppression of T and NK cell anti-tumor activity in EGFR-mutant NSCLC
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EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer
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IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC
Patel, S. A., Nilsson, M. B., Yang, Y., Le, X., Tran, H. T., Elamin, Y. Y., Yu, X., Zhang, F., Poteete, A., Ren, X., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3379 · Cited by 121 · see citing works

Authors: Gong, K., Guo, G., Panchani, N., Bender, M. E., Gerber, D. E., Minna, J. D., Fattah, F., Gao, B., Peyton, M., Kernstine, K., Mukherjee, B., Burma, S., Chiang, C.-M., Zhang, S., Amod Sathe, A., Xing, C., Dao, K. H., Zhao, D., Akbay, E. A., & Habib, A. A.
Affiliations: The University of Texas Southwestern Medical Center (US)
Harold C. Simmons Comprehensive Cancer Center (US)
Wake Forest University Health Sciences (US)
VA North Texas Health Care System (US)
Corresponding author: Habib, Amyn A.
ORCID: Gong, Ke
Guo, Gao
Bender, Matthew E.
Gerber, David E.
Minna, John D.
Fattah, Farjana
Gao, Boning
Peyton, Michael
Kernstine, Kemp
Mukherjee, Bipasha
Burma, Sandeep
Chiang, Cheng-Ming
Xing, Chao
Zhao, Dawen
Akbay, Esra A.
Habib, Amyn A.
Venue: Nature Cancer
Publisher: Springer Science and Business Media LLC
Published: 2020-04-06
Volume: 1
Issue: 4
Pages: 394-409
ISSN: 2662-1347 (ISSN-L)
DOI: 10.1038/s43018-020-0048-0
PMC: PMC7706867
OpenAlex: W3014320042
Cited by: 92
References: 63
Citations by year: 2026: 7 · 2025: 14 · 2024: 19 · 2023: 18 · 2022: 12 · 2021: 17 · 2020: 5
FWCI: 7.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Cancer (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Veterans Affairs (I01 BX002559)
National Institutes of Health (1s10od023552-01)
National Cancer Institute (R01CA197796, R01CA244212, R01CA103867, R01CA194578, P50CA070907, U01CA176284, K24CA201543, P30CA142543)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: EGFR inhibition, non-small cell lung cancer, type I interferon signaling, antiviral defense, RIG-I, TBK1, IRF3, TRIM32, K63-linked ubiquitination, NF-κB, EGFR tyrosine kinase inhibitors, KRAS mutation, drug resistance, combination therapy
MeSH terms: Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Signal Transduction, Protein Kinase Inhibitors, Cell Proliferation, Mice, ErbB Receptors

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