Targeting BRAFV600E in thyroid carcinoma:: therapeutic implications
Targeting BRAFV600E in thyroid carcinoma:: therapeutic implications
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DOI：
10.1158/1535-7163.mct-06-0449
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发表时间：
2007-03-01
影响因子：
5.7
通讯作者：
Mitsiades, Nicholas
中科院分区：
文献类型：
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作者：
Mitsiades, Constantine S.;Negri, Joseph;Mitsiades, Nicholas
B-Raf是通过Ras-Raf-MEK-ERK级联转导的细胞增殖和存活信号的重要介质。BRAF突变已在包括乳头状甲状腺癌在内的几种肿瘤中检测到，但B-Raf作为甲状腺癌治疗靶点的确切作用仍在研究中。我们分析了一组93例标本和14个甲状腺癌细胞系的BRAF突变和丝裂原活化蛋白/ERK激酶（MEK）/细胞外信号调节激酶（ERK）通路的激活。我们还比较了B-Raf小抑制性RNA构建体和B-Raf激酶抑制剂AAL 881对B-Raf野生型和突变型甲状腺癌细胞系的作用。我们发现T1799 A（V600 E）突变在乳头状癌和间变性癌标本和细胞系中的患病率很高。野生型和BRAF（V600 E）标本之间在患者年龄、B-Raf表达、Ki 67免疫染色或临床分期方面没有差异。磷酸化和总形式的MEK和ERK的免疫检测显示，野生型和BRAF（V600 E）患者标本或细胞系之间的磷酸化没有差异。此外，靶向野生型B-Raf和B-Raf（V600 E）表达的小抑制性RNA构建体在野生型和BRAF（V600 E）突变癌细胞中诱导了相当的活力降低。有趣的是，AAL 881抑制MEK和ERK磷酸化并诱导BRAF（V600 E）-窝藏细胞比野生型细胞的凋亡优先，可能是因为更好的抑制活性对B-Raf（V600 E）。我们的结论是，B-Raf是重要的甲状腺癌的病理生理，无论突变状态。选择性靶向B-Raf（V600 E）的小分子抑制剂可能为甲状腺癌患者提供临床获益。
B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF(V600E) specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF(V600E) patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf(V600E) induced a comparable reduction of viability in both wild-type and BRAF(V600E) mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF(V600E)-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf(V600E). We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf(V600E) may provide clinical benefit for patients with thyroid cancer.