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

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest. 2018 Apr 03;: Authors: Gong K, Guo G, E Gerber D, Gao B, Peyton M, Huang C, D Minna J, J Hatanpaa K, Kernstine K, Cai L, Xie Y, Zhu H, Fattah F, Zhang S, Takahashi M, Mukherjee B, Burma S, Dowell J, Dao K, A Papadimitrakopoulou V, Olivas V, G Bivona T, Zhao D, A Habib A 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 i...
Source: Clinical Lung Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research