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

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Abstract

Although aberrant Epidermal Growth Factor Receptor (EGFR) signaling is widespread in cancer, EGFR inhibition is effective only in a subset of NSCLC (non-small cell lung cancer) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. Tumor necrosis factor (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-kB activation leads to increased TNF transcription in a feedforward 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 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 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