@article{1bf01451fa814dada3a1a756af678c82,
title = "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-?B 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.",
author = "Ke Gong and Gao Guo and Gerber, {David E.} and Boning Gao and Michael Peyton and Chun Huang and Minna, {John D.} and Hatanpaa, {Kimmo J.} and Kemp Kernstine and Ling Cai and Yang Xie and Hong Zhu and Fattah, {Farjana J.} and Shanrong Zhang and Masaya Takahashi and Bipasha Mukherjee and Sandeep Burma and Jonathan Dowell and Kathryn Dao and Papadimitrakopoulou, {Vassiliki A.} and Victor Olivas and Bivona, {Trever G.} and Dawen Zhao and Habib, {Amyn A.}",
note = "Funding Information: This work was supported in part by NIH grant R01 NS062080 and by the Office of Medical Research at the Department of Veterans Affairs, a Lung Cancer SPORE Career Enhancement Program Award, and support from the Dallas VA Research Corporation to AAH. This work was also supported by National Cancer Institute Lung Cancer SPORE (P50CA70907), U01CA176284, and the Cancer Prevention Research Institute of Texas (RP110708) to JDM. This work was also supported by NIH grant 1R01CA194578 to DZ and by NIH grants R01CA169338 and U54CA224081 to TGB. DEG is supported by a National Cancer Institute Midcareer Investigator Award in Patient-Oriented Research, K24CA201543-01. SB is supported by grants from the NIH (RO1CA197796, RO1CA149461, and R21CA202403) and the National Aeronautics and Space Administration (NNX16AD78G). We thank Katerina Politi for generating and providing TetO-EGFR-L858R and CCSP-rtTA mice. We thank Jay Steer and David Joyce for TNF-UTR plasmid, Eric Haura for providing erlotinib-resistant cell lines, and Jessica Sal-tarski (UT Southwestern) for assistance in obtaining FFPE tissues.",
year = "2018",
month = jun,
day = "1",
doi = "10.1172/JCI96148",
language = "English (US)",
volume = "128",
pages = "2500--2518",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",
}