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Updated: Feb 2, 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
Leukocyte Cell-Derived Chemotaxin 2 Retards Non-Small Cell Lung Cancer Progression Through Antagonizing MET and EGFR
Wen-Yueh Hung1,2, Jer-Hwa Chang2,3, Yu Cheng1
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Background/Aims:
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is a clinical option for non-small cell lung cancer (NSCLC) harboring activating EGFR mutations or for cancer with wild-type (WT) EGFR when chemotherapy has failed. MET receptor activation or MET gene amplification was reported to be a major mechanism of acquired resistance to EGFR-TKI therapy in NSCLC cells. Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that was shown to suppress metastasis of hepatocellular carcinoma via inhibiting MET activity. Until now, the biological function responsible for LECT2's action in human NSCLC remains unclear.
Methods:
LECT2-knockout (KO) mice and NOD/SCID/IL2rgnull (NSG) mice were respectively used to investigate the effects of LECT2 on the tumorigenicity and metastasis of murine (Lewis lung carcinoma, LLC) and human (HCC827) lung cancer cells. The effect of LECT2 on in vitro cell proliferation was evaluated, using MTS and colony formation assays. The effect of LECT2 on cell motility was evaluated using transwell migration and invasion assays. An enzyme-linked immunosorbent assay was performed to detect secreted LECT2 in plasma and media. Co-immunoprecipitation and Western blot assays were used to investigate the underlying mechanisms of LECT2 in NSCLC cells.
Results:
Compared to WT mice, mice with LECT2 deletion exhibited enhanced growth and metastasis of LLC cells, and survival times decreased in LLC-implanted mice. Overexpression of LECT2 in orthotopic human HCC827 xenografts in NSG mice resulted in significant inhibition of tumor growth and metastasis. In vitro, overexpression of LECT2 or treatment with a recombinant LECT2 protein impaired the colony-forming ability and motility of NSCLC cells (HCC827 and PC9) harboring high levels of activated EGFR and MET. Mechanistic investigations found that LECT2 bound to MET and EGFR to antagonize their activation and further suppress their common downstream pathways: phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase.
Conclusion:
EGFR-MET signaling is critical for aggressive behaviors of NSCLC and is recognized as a therapeutic target for NSCLC especially for patients with acquired resistance to EGFR-TKI therapy. Our findings demonstrate, for the first time, that LECT2 functions as a suppressor of the progression of NSCLC by targeting EGFR-MET signaling.
Insights
Leukocyte cell-derived chemotaxin 2 (LECT2) suppresses non-small cell lung cancer (NSCLC) progression by targeting EGFR-MET signaling. This cytokine inhibits tumor growth and metastasis, offering a potential therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is used for non-small cell lung cancer (NSCLC) with EGFR mutations or wild-type (WT) EGFR after chemotherapy failure.
- MET receptor activation or amplification is a key mechanism of acquired resistance to EGFR-TKI therapy in NSCLC.
- Leukocyte cell-derived chemotaxin 2 (LECT2) inhibits MET activity and metastasis in hepatocellular carcinoma, but its role in NSCLC is unclear.
Purpose of the Study:
- To investigate the biological function of LECT2 in human non-small cell lung cancer (NSCLC).
- To determine the effect of LECT2 on tumorigenicity and metastasis of lung cancer cells.
- To elucidate the molecular mechanisms by which LECT2 influences NSCLC progression.
Main Methods:
- Utilized LECT2-knockout (KO) and NSG mice to study LECT2 effects on murine (LLC) and human (HCC827) lung cancer cells.
- Assessed in vitro cell proliferation (MTS, colony formation) and motility (transwell migration, invasion).
- Employed ELISA, co-immunoprecipitation, and Western blot assays to detect LECT2 and investigate molecular mechanisms.
Main Results:
- LECT2 deletion enhanced LLC tumor growth and metastasis in mice, reducing survival.
- LECT2 overexpression significantly inhibited tumor growth and metastasis in human HCC827 xenografts.
- LECT2 impaired NSCLC cell proliferation and motility by antagonizing EGFR-MET activation and downstream signaling (PI3K/Akt, ERK).
Conclusions:
- EGFR-MET signaling drives aggressive NSCLC behaviors and is a therapeutic target, particularly in acquired resistance to EGFR-TKI therapy.
- LECT2 acts as a suppressor of NSCLC progression by targeting the EGFR-MET signaling pathway.
- These findings highlight LECT2 as a potential therapeutic agent for NSCLC.
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