MET is a potential target for use in combination therapy with EGFR inhibition in triple‐negative/basal‐like breast cancer |
| |
Authors: | Jinwon Seo Ji‐Young Song Seung Eun Lee Mi Jung Kwon Mi Jeong Kwon Juthika Kundu Kyungsoo Jung Ensel Oh Young Kee Shin Yoon‐La Choi |
| |
Institution: | 1. Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi, Korea;2. Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea;3. Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea;4. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea;5. College of Pharmacy, Kyungpook National University, Daegu, Korea;6. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Korea;7. College of Pharmacy, Keimyung University, Daegu, Korea;8. Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Korea;9. Laboratory of Molecular Pathology and Cancer Genomics, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea |
| |
Abstract: | MET, a cell surface receptor for hepatocyte growth factor, is involved in the development of triple‐negative/basal‐like breast cancer (TNBC/BLBC). However, its utility as a therapeutic target in this subtype of breast cancer is poorly understood. To evaluate MET fully as a potential therapeutic target for TNBC/BLBC, we investigated the relationship between MET expression and clinical outcomes of patients with breast cancer and the functional effect of MET inhibition. Using automated immunohistochemistry (Ventana), we analyzed MET expression in 924 breast cancer patients with relevant clinicopathologic parameters. BLBC showed the strongest relationship with MET expression (57.5%, p < 0.001). High expression of MET in breast cancer resulted in poor overall survival (p = 0.001) and disease‐free survival (DFS, p = 0.010). MET expression was relatively high in TNBC cell lines, and the silencing of MET via small interfering RNA reduced cell proliferation and migration. We observed reduced TNBC cell viability after treatment with the MET inhibitor PHA‐665752. In the most drug‐resistant cell line, MDA‐MB‐468, which showed elevated epidermal growth factor receptor (EGFR) expression, silencing of EGFR resulted in increased sensitivity to PHA‐665752 treatment. We confirmed that PHA‐665752 synergizes with the EGFR inhibitor erlotinib to decrease the viability of MDA‐MB‐468 cells. TNBC patients coexpressing MET and EGFR showed significantly worse DFS than that in patients expressing EGFR alone (p = 0.021). Our findings strongly suggest that MET may be a therapeutic target in TNBC and that the combined therapy targeting MET and EGFR may be beneficial for the treatment of TNBC/BLBC patients. |
| |
Keywords: | MET epidermal growth factor receptor breast cancer triple‐negative basal‐like |
|
|