TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer
Ke Gong, … , Dawen Zhao, Amyn A. Habib
Ke Gong, … , Dawen Zhao, Amyn A. Habib
Published April 3, 2018
Citation Information: J Clin Invest. 2018;128(6):2500-2518. https://doi.org/10.1172/JCI96148.
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Research Article

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer

Abstract

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non–small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.

Authors

Ke Gong, Gao Guo, David E. Gerber, Boning Gao, Michael Peyton, Chun Huang, John D. Minna, Kimmo J. Hatanpaa, Kemp Kernstine, Ling Cai, Yang Xie, Hong Zhu, Farjana J. Fattah, Shanrong Zhang, Masaya Takahashi, Bipasha Mukherjee, Sandeep Burma, Jonathan Dowell, Kathryn Dao, Vassiliki A. Papadimitrakopoulou, Victor Olivas, Trever G. Bivona, Dawen Zhao, Amyn A. Habib

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Figure 8

Combined inhibition of EGFR and TNF in mouse models.

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Combined inhibition of EGFR and TNF in mouse models. (A) Athymic mice we...
(A) Athymic mice were injected s.c. with 1 × 106 A549 cells. When tumors formed, mice were randomly divided into 4 groups (control, erlotinib, thalidomide, and erlotinib plus thalidomide, n = 8). The mice were treated with 100 mg/kg erlotinib by oral gavage and/or i.p. injection of 150 mg/kg thalidomide for 10 consecutive days. (B) HCC4087 EGFRwt NSCLC PDX was implanted s.c. into NOD/SCID mice. When tumors formed, mice were divided into 4 groups (n = 12) and treated with 100 mg/kg erlotinib or 150 mg/kg thalidomide for 28 days. (C) This experiment was conducted with HCC827 cells (n = 8), and mice were treated with erlotinib (10 mg/kg/day) and/or thalidomide (150 mg/kg/day). (D) Two A549 clones with stable TNF silencing were identified and have low basal and LPS-induced TNF (#16 and #23). n = 3 biologically independent experimental replicates. ***P < 0.001, 2-sample t test. (E) A549 cells with stably silenced TNF (clone 16) or control shRNA were implanted in flanks of athymic mice. When tumors formed, mice were grouped into control shRNA, TNF shRNA, control shRNA + afatinib, and TNF shRNA + afatinib (n = 6). Afatinib (25 mg/kg) was provided by oral gavage. (F) Athymic mice were injected s.c. with A549 cells. When tumors formed, mice were divided into 4 groups (control, afatinib, thalidomide, afatinib plus etanercept, n = 6). The mice were treated by oral gavage of 25 mg/kg afatinib and/or 3 mg/kg etanercept i.p. Each data point represents the mean tumor volume ± SEM. Statistical significance was defined as P < 0.05 (repeated-measures 2-way ANOVA, Bonferroni correction for adjusting multiple comparisons, between EGFR inhibition group and combination of EGFR and TNF inhibition group, by GraphPad Prism 7.0). **P < 0.01, ***P < 0.001.