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Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations
Open accessPublished version of a preprint
Abstract
Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.
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“Activation of MET by its ligand hepatic growth factor (HGF) was also sufficient to promote resistance through activation of downstream signaling (Yano et al., 2008).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Yano et al., 2008
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Metadata
- Authors
- Yano, S., Wang, W., Li, Q., Matsumoto, K., Sakurama, H., Nakamura, T., Ogino, H., Kakiuchi, S., Hanibuchi, M., Nishioka, Y., Uehara, H., Mitsudomi, T., Yatabe, Y., Nakamura, T., & Sone, S.
- Affiliations
- 1Medical Oncology and Divisions of
- Kanazawa University (JP)
- 3Respiratory Medicine and Rheumatology and
- Tokushima University (JP)
- 5Thoracic Surgery and
- Aichi Cancer Center Hospital (JP)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-11-14
- Volume
- 68
- Issue
- 22
- Pages
- 9479-9487
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2119351872
- Cited by
- 643
- References
- 39
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 11 · 2023: 29 · 2022: 12 · 2021: 33 · 2020: 22 · 2019: 23 · 2018: 43 · 2017: 47 · 2016: 38 · 2015: 52 · 2014: 67 · 2013: 71 · 2012: 58
- FWCI
- 33.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- hepatocyte growth factor, gefitinib resistance, lung adenocarcinoma, EGFR activating mutations, phosphatidylinositol 3-kinase/Akt signaling, EGFR tyrosine kinase inhibitors, HGF/MET signaling, T790M mutation, MET amplification
- MeSH terms
- Gefitinib, Adenocarcinoma, Humans, Lung Neoplasms, Mutation, Phosphorylation, Proto-Oncogene Proteins, Quinazolines, Hepatocyte Growth Factor, Receptors, Growth Factor, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Receptor, ErbB-3, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, ErbB Receptors
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