Gautam Shailendra K, Kanchan Ranjana K, Siddiqui Jawed A, Maurya Shailendra K, Rauth Sanchita, Perumal Naveenkumar, Atri Pranita, Venkata Ramakanth C, Mallya Kavita, Mirza Sameer, Ponnusamy Moorthy P, Band Vimla, Mahapatra Sidharth, Jain Maneesh, Batra Surinder K, Nasser Mohd Wasim
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cancers (Basel). 2020 Oct 1;12(10):2838. doi: 10.3390/cancers12102838.
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.
脑转移（BrM）仍然是表皮生长因子受体2阳性（ERBB2）乳腺癌（BC）患者癌症相关死亡的重要原因。我们在此提出，不可逆酪氨酸激酶抑制剂奈拉替尼（NER）与c-MET抑制剂卡博替尼（CBZ）联合治疗可预防脑转移。为解决这一问题，我们首先在具有脑趋向性的ERBB2细胞系SKBrM3和JIMT-1-BR3以及表达c-MET/ERBB1轴的ERBB2类器官中测试了NER和CBZ的联合治疗。接下来，我们建立并表征了自发性BrM的原位小鼠模型，并在体内评估了CBZ和NER的治疗效果。NER和CBZ联合治疗显著抑制了ERBB2细胞系的增殖和迁移，并减少了体外类器官的生长。从机制上讲，NER和CBZ联合治疗显著抑制了c-MET/ERBB1轴下游的ERK激活。原位植入的SKBrM3细胞在乳腺脂肪垫中形成原发性肿瘤，并自发转移至脑和其他远处器官。NER和CBZ联合治疗抑制了原发性肿瘤生长，并主要预防了BrM。总之，自发性BrM的原位模型具有临床相关性，NER和CBZ联合治疗可能是预防BC患者BrM的一种有效方法。
