Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement.
Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement.
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DOI：
10.1158/1078-0432.ccr-07-1772
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发表时间：
2008-08-01
期刊：
影响因子：
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通讯作者：
Clayman GL
中科院分区：
文献类型：
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作者：
Henderson YC;Ahn SH;Kang Y;Clayman GL
甲状腺乳头状癌（PTC）是最常见的甲状腺恶性肿瘤类型，具有两种突变之一，RET/PTC重排或BRAF突变。这两种突变都能够激活MEK/ERK信号转导通路，并导致调节细胞增殖、分化和凋亡的转录因子的激活。索拉非尼（Nexavar，BAY 43-9006）是一种多激酶抑制剂，在这项研究中，我们测试了它对携带任一突变的PTC细胞的影响。使用生长曲线、细胞周期分析和免疫印迹法在体外对PTC细胞评价索拉非尼对细胞增殖和信号传导的影响。使用原位小鼠模型，我们确定了索拉非尼在体内的抗肿瘤作用。对于RET/PTC 1重排的PTC细胞，索拉非尼50%生长抑制所需的浓度（GI 50）为0.14 μmol/L，对于BRAF突变的PTC细胞，索拉非尼50%生长抑制所需的浓度为2.5 μmol/L，这两种浓度均容易达到血清浓度。小鼠口服索拉非尼（80 mg/kg/d）3周后，在接种携带RET/PTC 1重排的PTC细胞的小鼠中检测到较小（与对照组相比减少94%）或无肿瘤生长，而具有BRAF突变的PTC细胞的原位肿瘤植入物的肿瘤体积减少53%至54%（与对照组相比）。携带RET/PTC 1重排的PTC细胞比携带BRAF突变的PTC细胞对索拉非尼更敏感。由于RET/PTC重排是甲状腺癌特有的，我们的研究结果支持索拉非尼对PTC患者的临床评价，并确定最有可能对索拉非尼治疗有反应的患者。
Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy with one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the MEK/ERK signaling transduction pathway and result in the activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Sorafenib (Nexavar, BAY 43-9006) is a multikinase inhibitor, and in this study, we tested its effects on PTC cells carrying either mutation. The effects of sorafenib on cell proliferation and signaling were evaluated in vitro on PTC cells using growth curves, cell cycle analysis, and immunoblotting. Using an orthotopic mouse model, we determined the antitumor effects of sorafenib in vivo. The concentration needed for 50% growth inhibition (GI50) by sorafenib was 0.14 μmol/L for the PTC cells with the RET/PTC1rearrangement, and 2.5 μmol/L for PTC cells with a BRAF mutation, both readily achievable serum concentrations. After 3 weeks of oral administration of sorafenib (80 mg/kg/d) in mice, small (94% reduction compared with controls) or no tumor growth was detected in mice inoculated with PTC cells bearing the RET/PTC1 rearrangement, whereas the tumor volume of the orthotopic tumor implants of PTC cells with a BRAF mutation was reduced 53% to 54% (as compared with controls). PTC cells carrying the RET/PTC1rearrangement were more sensitive to sorafenib than PTC cells carrying a BRAF mutation. Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.