Abstract
Simple SummaryTargeted monotherapies are ineffective in the treatment of brain metastasis of ERBB2+ breast cancer (BC) underscoring the need for combination therapies. The lack of robust preclinical models has further hampered the assessment of treatment modalities. We report here a clinically relevant orthotopic mouse model of ERBB2+ BC that spontaneously metastasizes to brain and demonstrates that targeting the c-MET/ERBB1 axis with a combination of cabozantinib and neratinib decreases primary tumor growth and prevents brain metastasis in ERBB2+ BC.Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC.
Highlights
The improved five-year survival rate of ~90% of breast cancer (BC) patients is mainly attributed to its successful clinical management that includes early screening and effective treatment modalities [1].for BC patients with distant metastasis, the five-year survival rate is ~27%, with a median survival of 18–24 months [2]
Previous reports suggest that ERBB1/2 and c-MET pathways play an important role in metastatic progression of different cancers, including BC [26,27,28,29]
We analyzed the expression of ERBB1, ERBB2, and c-MET receptors in the ERBB2+ brain metastatic BC cell lines SKBrM3 and JIMT-1-BR3
Summary
The improved five-year survival rate of ~90% of breast cancer (BC) patients is mainly attributed to its successful clinical management that includes early screening and effective treatment modalities [1].for BC patients with distant metastasis, the five-year survival rate is ~27%, with a median survival of 18–24 months [2]. The poor therapeutic response towards targeted therapies in metastatic ERBB2+ BC is attributed in part to clonal evolution in metastatic cells, their adaptation to the organ-specific microenvironment, and differential drug delivery to the metastatic niche [4,5,6]. This is exemplified by the presence of the blood–brain barrier (BBB) in the case of BrM, which has one of the poorest outcomes among all metastatic BCs [7,8,9]
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