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Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers
- Source :
- Journal of Cancer Research and Clinical Oncology. 148:2995-3005
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- PURPOSE Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). METHODS Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. RESULTS A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7 months, respectively, for PFS (p = 0.009), and median 21.1 months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. CONCLUSION Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.
- Subjects :
- Proto-Oncogene Proteins B-raf
Neuroblastoma RAS viral oncogene homolog
Cancer Research
Colorectal cancer
Cetuximab
medicine.disease_cause
GTP Phosphohydrolases
Proto-Oncogene Proteins p21(ras)
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
neoplasms
EGFR inhibitors
Hepatocyte Growth Factor
Triazines
business.industry
Imidazoles
Membrane Proteins
General Medicine
medicine.disease
digestive system diseases
Bevacizumab
ErbB Receptors
Oncology
Benzamides
Mutation
Cancer research
FOLFIRI
Biomarker (medicine)
Hepatocyte growth factor
KRAS
Caco-2 Cells
Colorectal Neoplasms
business
Proto-Oncogene Proteins c-akt
medicine.drug
Subjects
Details
- ISSN :
- 14321335 and 01715216
- Volume :
- 148
- Database :
- OpenAIRE
- Journal :
- Journal of Cancer Research and Clinical Oncology
- Accession number :
- edsair.doi.dedup.....c70a62d8a3145d10f53940b1ad0da76f