MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo.
MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo.
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DOI：
10.1158/1535-7163.mct-10-0062
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发表时间：
2010-07
影响因子：
5.7
通讯作者：
Clayman GL
中科院分区：
文献类型：
--
作者：
Henderson YC;Chen Y;Frederick MJ;Lai SY;Clayman GL
甲状腺乳头状癌（PTC）是最常见的甲状腺恶性肿瘤。大多数PTC携带两种突变之一，RET/PTC重排或BRAF突变。两种突变都能够激活促分裂原活化蛋白激酶激酶/细胞外信号调节激酶（MEK/ERK）信号转导途径，导致细胞增殖、分化和凋亡。PD 0325901是一种特异性的MEK 1/2抑制剂，因此是一种有前途的治疗RET/PTC或BRAF突变的甲状腺癌的药物。在这项研究中，我们测试了PD 0325901对PTC细胞的影响，无论是在体外通过生长曲线和蛋白质印迹突变，并在体内使用小鼠原位异种移植模型。我们发现，对于RET/PTC 1重排的PTC细胞，PD 0325901的50%生长抑制（GI 50）为11 nmol/L，对于BRAF突变的PTC细胞，为6.3 nmol/L，两种浓度在血清中均可达到。小鼠经口给予PD 0325901（20-25 mg/kg/天）1周后，在接种携带BRAF突变的PTC细胞的小鼠中未检测到肿瘤生长。对于具有RET/PTC 1重排的PTC，与对照相比，原位肿瘤的平均肿瘤体积减少了58%。总之，我们的数据表明，携带BRAF突变的PTC细胞比携带RET/PTC 1重排的PTC细胞对PD 0325901更敏感。我们的研究结果支持PD 0325901对PTC和其他BRAF突变癌患者的临床评价。
Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy. Most PTC carry one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling transduction pathway leading to cellular proliferation, differentiation, and apoptosis. PD0325901 is a specific MEK1/2 inhibitor and therefore is a promising drug to treat thyroid cancers with either RET/PTC or BRAF mutation. In this study we tested the effects of PD0325901 on PTC cells harboring either mutation in vitro by growth curves and Western blots and in vivo using a murine orthotopic xenograft model. We found that 50% growth inhibition (GI50) by PD0325901 was 11 nmol/L for the PTC cells with the RET/PTC1 rearrangement and 6.3 nmol/L for PTC cells with a BRAF mutation, with both concentrations readily achievable in serum. After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth was detected in mice inoculated with PTC cells bearing a BRAF mutation. For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor was reduced by 58% as compared with controls. In conclusion, our data suggested that PTC cells carrying a BRAF mutation were more sensitive to PD0325901 than were PTC cells carrying the RET/PTC1 rearrangement. Our findings support the clinical evaluation of PD0325901 for patients with PTC and potentially other carcinomas with BRAF mutations.