Related Experiment Video
Updated: Feb 12, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer
Ke Gong1, Gao Guo1, David E Gerber2,3
1Department of Neurology and Neurotherapeutics.
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.
Insights
Blocking TNF enhances EGFR inhibition effectiveness in non-small cell lung cancer (NSCLC). Combining EGFR and TNF inhibitors may benefit most lung cancer patients, including those with wild-type EGFR or resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aberrant epidermal growth factor receptor (EGFR) signaling drives many cancers, but EGFR inhibition benefits only a subset of non-small cell lung cancer (NSCLC) with specific mutations.
- The majority of NSCLC cases express wild-type EGFR (EGFRwt) and are resistant to EGFR-targeted therapies.
- Tumor necrosis factor (TNF) is a key mediator in inflammation-driven cancers and its role in EGFR inhibitor response is under investigation.
Purpose of the Study:
- To investigate the adaptive response to EGFR inhibition in NSCLC.
- To elucidate the role of TNF in mediating resistance to EGFR inhibitors in NSCLC.
- To evaluate the potential of combined EGFR and TNF inhibition as a novel therapeutic strategy for NSCLC.
Main Methods:
- Analysis of TNF levels in response to EGFR inhibition across different NSCLC subtypes.
- Investigated the regulatory role of miR-21 in TNF mRNA stability and EGFR signaling.
- Assessed the efficacy of combined EGFR and TNF inhibition in EGFRwt NSCLC cell lines, patient-derived xenografts (PDXs), and models with acquired resistance.
Main Results:
- EGFR inhibition universally triggers a rapid increase in TNF levels in NSCLC, irrespective of EGFR mutation status.
- EGFR signaling suppresses TNF by upregulating miR-21, which decreases TNF mRNA stability; EGFR inhibition reverses this effect, increasing TNF stability and transcription via an NF-κB feedback loop.
- Inhibition of TNF signaling sensitized EGFRwt NSCLC models to EGFR inhibitors and enhanced the efficacy of EGFR inhibitors in EGFR-mutant NSCLC and in models with acquired resistance.
Conclusions:
- Combined inhibition of EGFR and TNF represents a promising therapeutic strategy for a broad spectrum of NSCLC patients.
- This approach could overcome primary resistance in EGFRwt NSCLC and acquired resistance in EGFR-mutant NSCLC.
- Targeting the EGFR-TNF axis offers a potential new treatment paradigm for the majority of lung cancer patients.
Related Concept Videos
01:23Cells of the Adaptive Immune Response
02:56Treatment Resistant Cancers
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:40Cell-mediated Immune Responses
00:46Feedback Inhibition
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...