BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines
BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines
复制标题
DOI：
10.1210/jc.2007-2825
复制
发表时间：
2008-06-01
影响因子：
5.8
通讯作者：
Fagin, James A.
中科院分区：
文献类型：
--
作者：
Leboeuf, Rebecca;Baumgartner, Jacqueline E.;Fagin, James A.
背景：约 70% 的甲状腺乳头状癌中存在 RET、RAS 或 BRAF 的互斥突变，而低分化癌和间变性癌中仅发现后两种突变。尽管这些癌蛋白共同的信号输出是 ERK，但最近的一份报告表明，只有 BRAF 突变一致预测对 MAPK 激酶 (MEK) 抑制剂的反应。 目的：在这里，我们研究了 13 种人类甲状腺癌细胞系中对 MEK 抑制的敏感性是否由癌基因状态决定：四种 BRAF 突变、四种 RAS、一种 RET/PTC1 和四种野生型。 结果：BRAF 的生长 (+) 细胞被 MEK 拮抗剂 PD0325901 抑制，IC50 小于 5nM。相比之下，RAS、RET/PTC1 或野生型细胞的 IC50 为 4nM 至大于 1000nM。 PIK3CA 共存突变或 PTEN 状态无法预测敏感性。 MEK 抑制剂 AZD6244 也获得了类似的效果。 PD0325901 在 BRAF (+) 系中诱导持续的 G1/S 阻滞，但在 BRAF (-) 系中则不然。无论遗传背景如何，PD0325901 在 2 小时后抑制 pERK1/2 的能力是等效的，但在大多数品系中，pERK 在 24 小时后反弹。 MEK 抑制剂耐药性与 pERK 对化合物进一步抑制的部分耐药性相关。 AZD6244 比 Cal62 (KRAS +) 异种移植物更能有效抑制 NPA (BRAF +) 的生长。结论：具有 BRAF 突变的甲状腺癌优先对 MEK 抑制剂敏感，而具有其他 MEK-ERK 效应通路基因突变的肿瘤则具有不同的反应，要么是因为它们仅部分依赖于 ERK 和/或因为反馈反应引发 对 MEK 抑制部分无效。
Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors.Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/PTC1, and four wild type.Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC50 of less than 5nM. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4nM to greater than 1000nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts.Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition.