Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis.
Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis.
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DOI：
10.1158/1078-0432.ccr-11-3359
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发表时间：
2012-07-01
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影响因子：
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通讯作者：
Schweppe RE
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文献类型：
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作者：
Chan CM;Jing X;Pike LA;Zhou Q;Lim DJ;Sams SB;Lund GS;Sharma V;Haugen BR;Schweppe RE
对于低分化甲状腺乳头状癌（PTC）或甲状腺间变性癌（ATC）患者没有有效的治疗方法，并且骨转移代表了明显更差的预后。Src家族激酶（SFK）在许多肿瘤类型中过表达和活化，并且已经成为有希望的治疗靶点，特别是与转移有关。我们最近发现Src在甲状腺癌中过度表达和激活。因此，我们测试了用达沙替尼（BMS-354825）抑制Src是否阻断甲状腺癌生长和转移。在体外评价了达沙替尼对甲状腺癌生长、信号传导、细胞周期和凋亡的影响。使用原位和新型实验转移模型在体内进一步测试达沙替尼的治疗功效。表征了甲状腺癌细胞中SFKs的表达和活化，并使用Src看门突变体确定了达沙替尼的选择性。达沙替尼治疗抑制Src信号传导，降低生长，并诱导甲状腺癌细胞亚群的细胞周期停滞和凋亡。免疫印迹显示c-Src和林恩在甲状腺癌细胞中表达，并且c-Src是主要的SFK活化。在原位模型中，达沙替尼治疗阻断PTC肿瘤生长超过90%（P = 0.0014）。达沙替尼的辅助和后治疗方法显著抑制了转移（分别为P = 0.016和P = 0.004）。这些数据提供了Src是甲状腺癌生长和转移的中心介质的第一个证据，表明Src抑制剂作为抗肿瘤和抗转移剂在甲状腺癌中可能具有更高的治疗功效。
There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant. Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively). These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.