Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma
Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma
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DOI：
10.1002/ijc.32180
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发表时间：
2019-08-15
影响因子：
6.4
通讯作者：
Cai, Zhengdong
中科院分区：
文献类型：
--
作者：
Wang, Gangyang;Sun, Mengxiong;Cai, Zhengdong
骨肉瘤是儿童和青少年中最常见的原发性恶性骨肿瘤，具有高度侵袭性和早期全身转移。在过去的二十年里，骨肉瘤的存活率保持不变。研究旨在寻找新的或替代疗法的难治性骨肉瘤患者是迫切需要的。Anlotinib是一种新型的多靶点酪氨酸激酶抑制剂（TKI），在非slcc和软组织肉瘤中显示出令人鼓舞的临床活性，而其对骨肉瘤的作用尚未研究。在我们的研究中，我们研究了安洛替尼在骨肉瘤中的抗肿瘤活性及其机制。采用各种体外和体内人骨肉瘤模型，测定安洛替尼的抗增殖、抗血管生成和抗转移效果。我们的研究结果表明，安洛替尼抑制肿瘤生长，增加骨肉瘤的化疗敏感性。此外，安洛替尼抑制骨肉瘤细胞的迁移和侵袭。此外，为了探索anlotinib的抗肿瘤机制，我们进行了phospho-RTK抗体阵列实验。这些分析证实，anlotinib抑制MET、VEGFR2的磷酸化和下游信号通路的激活。此外，我们证明了anlotinib阻断肝细胞生长因子（HGF）诱导的细胞迁移、侵袭和vegf诱导的血管生成。值得注意的是，143B-Luc原位骨肉瘤模型进一步表明，安洛替尼显著抑制植入肿瘤细胞的生长和肺转移。我们的临床前工作表明，anlotinib作为一种新的VEGFR2和MET抑制剂，可以阻断骨肉瘤的肿瘤发生，这可以转化为未来的临床试验。
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with highly aggressive behavior and early systemic metastasis. The survival rates for osteosarcoma remain unchanged over the past two decades. Studies aiming to find new or alternative therapies for patients with refractory osteosarcoma are urgently needed. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging clinical activity in NSLCC and soft tissue sarcoma, whereas its effect on osteosarcoma has not been studied. In our study, we investigated the anti-tumor activity and underlying mechanism of anlotinib in osteosarcoma. Various in vitro and in vivo models of human osteosarcoma were used to determine the anti-proliferative, anti-angiogenesis and anti-metastasis efficacy of anlotinib. Our results showed that anlotinib suppressed tumor growth and increased the chemo-sensitivity of osteosarcoma. In addition, anlotinib inhibited migration and invasion in osteosarcoma cells. Furthermore, in order to explore the anti-tumor mechanism of anlotinib, phospho-RTK antibody arrays were performed. These analyses confirmed that anlotinib suppressed the phosphorylation of MET, VEGFR2 and the downstream signaling pathway activation. Moreover, we demonstrated that anlotinib blocked hepatocyte growth factor (HGF)-induced cell migration, invasion and VEGF-induced angiogenesis. Notably, a 143B-Luc orthotopic osteosarcoma model further showed that anlotinib significantly inhibited growth and lung metastasis of implanted tumor cells. Our preclinical work indicates that anlotinib acts as a novel inhibitor of VEGFR2 and MET that blocks tumorigenesis in osteosarcoma, which could be translated into future clinical trials.