MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

作者：Kim Yu Jin; Choi Jong Sun; Seo Jinwon; Song Ji Young; Lee Seung Eun; Kwon Mi Jung; Kwon Mi Jeong; Kundu Juthika; Jung Kyungsoo; Oh Ensel; Shin Young Kee; Choi Yoon La^*

来源：International Journal of Cancer, 2014, 134(10): 2424-2436.

DOI：10.1002/ijc.28566

• MET
• epidermal growth factor receptor
• breast cancer
• triple-negative
• basal-like

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%26lt;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. %26lt;br%26gt;What%26apos;s new? Although aberrant activity of MET, a cell-surface receptor for hepatocyte growth factor (HGF), has been reported in triple-negative/basal-like breast cancer (TNBC/BLBC), its potential as a therapeutic target for the disease remains unknown. Here, treatment of high MET-expressing TNBC cell lines with the MET inhibitor PHA-665752 was found to reduce TNBC cell viability, while silencing of MET with small interfering RNA led to reduced cell proliferation and migration. In the drug-resistant cell line MDA-MB-468, silencing of epidermal growth factor receptor (EGFR) resulted in increased sensitivity to anti-MET therapy, suggesting that both MET and EGFR could be targeted in TNBC/BLBC.

• 出版日期2014-5-15