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.

Original languageEnglish (US)
Pages (from-to)2500-2518
Number of pages19
JournalJournal of Clinical Investigation
Volume128
Issue number6
DOIs
StatePublished - Jun 1 2018

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
RNA Stability
Inflammation Mediators
Oncogenes
Heterografts
Neoplasms
Cell Line
Messenger RNA
Mutation
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. / Gong, Ke; Guo, Gao; Gerber, David E.; Gao, Boning; Peyton, Michael; Huang, Chun; Minna, John D.; Hatanpaa, Kimmo J.; Kernstine, Kemp; Cai, Ling; Xie, Yang; Zhu, Hong; Fattah, Farjana J.; Zhang, Shanrong; Takahashi, Masaya; Mukherjee, Bipasha; Burma, Sandeep; Dowell, Jonathan; Dao, Kathryn; Papadimitrakopoulou, Vassiliki A.; Olivas, Victor; Bivona, Trever G.; Zhao, Dawen; Habib, Amyn A.

In: Journal of Clinical Investigation, Vol. 128, No. 6, 01.06.2018, p. 2500-2518.

Research output: Contribution to journalArticle

Gong, Ke ; Guo, Gao ; Gerber, David E. ; Gao, Boning ; Peyton, Michael ; Huang, Chun ; Minna, John D. ; Hatanpaa, Kimmo J. ; Kernstine, Kemp ; Cai, Ling ; Xie, Yang ; Zhu, Hong ; Fattah, Farjana J. ; Zhang, Shanrong ; Takahashi, Masaya ; Mukherjee, Bipasha ; Burma, Sandeep ; Dowell, Jonathan ; Dao, Kathryn ; Papadimitrakopoulou, Vassiliki A. ; Olivas, Victor ; Bivona, Trever G. ; Zhao, Dawen ; Habib, Amyn A. / TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 6. pp. 2500-2518.
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AU - Huang, Chun

AU - Minna, John D.

AU - Hatanpaa, Kimmo J.

AU - Kernstine, Kemp

AU - Cai, Ling

AU - Xie, Yang

AU - Zhu, Hong

AU - Fattah, Farjana J.

AU - Zhang, Shanrong

AU - Takahashi, Masaya

AU - Mukherjee, Bipasha

AU - Burma, Sandeep

AU - Dowell, Jonathan

AU - Dao, Kathryn

AU - Papadimitrakopoulou, Vassiliki A.

AU - Olivas, Victor

AU - Bivona, Trever G.

AU - Zhao, Dawen

AU - Habib, Amyn A.

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N2 - 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.

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