Breast Cancer-Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown
Breast Cancer-Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown
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DOI：
10.1158/1535-7163.mct-11-0277
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发表时间：
2012-01-01
影响因子：
5.7
通讯作者：
Broggini, Massimo
中科院分区：
文献类型：
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作者：
Previdi, Sara;Abbadessa, Giovanni;Broggini, Massimo
乳腺癌表现出转移到骨的倾向，导致与显著发病率和不良预后相关的使人衰弱的骨骼并发症。转移性癌细胞与骨之间的相互作用对于骨转移的发展和进展至关重要。我们已经表明HGF/c-MET系统参与肿瘤-骨相互作用，从而促进人乳腺癌转移。因此，破坏HGF/c-MET信号传导是治疗转移性骨疾病的潜在靶向方法。在这项研究中，我们评估了口服选择性小分子c-MET抑制剂tivantinib和针对c-MET的特异性短发夹RNA（shRNA）在人乳腺癌小鼠模型中对c-MET的抑制作用。Tivantinib在体内表现出剂量依赖性抗转移活性，120 mg/kg剂量（已证明在减少皮下肿瘤生长方面次优）可显著抑制骨中乳腺癌细胞的转移性生长，并显著减少肿瘤诱导的骨质溶解。shRNA介导的c-MET沉默不影响骨转移细胞的体外增殖，但显著降低了其迁移，而tivantinib进一步增强了这种作用。这两种观察结果均在体内得到证实。事实上，通过使用tivantinib和RNA干扰策略的双重c-MET抑制，实现了更明显的肿瘤生长抑制，伴随着溶解性病变的显著减少和生存期的延长。总体而言，我们的研究结果强调了c-MET抑制在延迟骨转移的发生和进展方面的有效性，并强烈表明靶向c-MET在治疗乳腺癌骨转移中可能具有有希望的治疗价值。Mol Cancer Ther; 11（1）; 214-23. (C)2011年AACR。
Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor-bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA(shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer. Mol Cancer Ther; 11(1); 214-23. (C) 2011 AACR.