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 Therapeutics

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 1

Upregulation of TNF signaling by EGFR inhibition.

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Upregulation of TNF signaling by EGFR inhibition. (A–F) NSCLC cell lines...
(A–F) NSCLC cell lines were cultured in RPMI-1640 in 5% FBS and were treated with erlotinib for the times indicated followed by RNA extraction and quantitative PCR (qPCR) for TNF. (G and H) Cells were treated with erlotinib, and the TNF level was measured in the supernatant by ELISA. (I and J) Athymic mice were injected s.c. with HCC827 cells. After formation of tumors, erlotinib at the dose of 50 mg/kg body weight was administered for the times indicated followed by removal of tumor and quantitation of TNF mRNA by qPCR or protein by ELISA. (K and L) Athymic mice were injected s.c. with A549 cells. After formation of tumors, erlotinib at 100 mg/kg body weight was administered for the times indicated followed by removal of tumor and quantitation of TNF mRNA by qPCR or protein by ELISA. Since the TNF level remained high at 7 days in these cells, we added an additional time point at 14 days (n = 3 mice per group). (M and N) NOD/SCID mice were implanted s.c. with HCC4087 PDX tumor tissues. After formation of tumors, erlotinib at 100 mg/kg body weight was given to the mice for 0, 1, 2, 4, 7, and 14 days; then mice were sacrificed and tumors were removed for quantitation of TNF mRNA by qPCR or protein by ELISA (n = 3 mice per group). Data represent the mean ± SEM. n = 3 biologically independent experimental replicates (A–H) or 3 mice per group (I–N). *P < 0.05, **P < 0.01, ***P < 0.001, by Student’s t test.