Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases
Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases
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DOI：
10.1158/1535-7163.mct-06-0084
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Herlyn, M
中科院分区：
文献类型：
--
作者：
Smalley, KSM;Haass, NK;Herlyn, M
尽管> 66%的黑素瘤在BRAF中具有活化突变并且在促分裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）/细胞外信号调节激酶信号传导途径中表现出组成性活性，但不清楚MEK抑制作为黑素瘤的唯一治疗策略将如何有效。我们在一组来源于原发性黑色素瘤和转移性黑色素瘤的径向生长期（WM 35）和垂直生长期（WM 793）的细胞系中研究了MEK抑制的抗癌活性（1205Lu，451Lu，WM 164，和C8161），并发现转移系对MEK抑制完全耐受（U 0126和PD 98059），但早期细胞系没有。类似地，这些相同的转移性黑色素瘤细胞系也对磷脂酰肌醇3-激酶/ Akt途径的抑制剂（LY 294002和渥曼青霉素）具有抗性。在贴壁培养条件下，MEK抑制剂通过诱导细胞周期停滞和上调p27来阻断生长，但这在抑制剂洗脱后容易逆转。然而，当磷脂酰肌醇3-激酶和MEK抑制剂组合时，转移性黑色素瘤三维球体的生长和侵袭被阻断。综上所述，这些结果表明，最具侵袭性的黑色素瘤对靶向一种信号通路的策略具有抗性，并且可能需要靶向多种信号通路以获得最大的治疗效果。进一步表明BRAF突变状态不能预测在三维培养条件下对MEK抑制的响应。
Although > 66% of melanomas harbor activating mutations in BRAF and exhibit constitutive activity in the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway, it is unclear how effective MEK inhibition will be as a sole therapeutic strategy for melanoma. We investigated the anticancer activity of MEK inhibition in a panel of cell lines derived from radial growth phase (WM35) and vertical growth phase (WM793) of primary melanomas and metastatic melanomas (1205Lu, 451Lu, WM164, and C8161) in a three-dimensional spheroid model and found that the metastatic lines were completely resistant to MEK inhibition (U0126 and PD98059) but the earlier stage cell lines were not. Similarly, these same metastatic melanoma lines were also resistant to inhibitors of the phosphatidylinositol 3-kinase/ Akt pathway (LY294002 and wortmannin). Under adherent culture conditions, the MEK inhibitors blocked growth through the induction of cell cycle arrest and up-regulation of p27, but this was readily reversible following inhibitor washout. However, when the phosphatidylinositol 3-kinase and MEK inhibitors were combined, the growth and invasion of the metastatic melanoma three-dimensional spheroids were blocked. Taken together, these results suggest that the most aggressive melanomas are resistant to strategies targeting one signaling pathway and that multiple signaling pathways may need to be targeted for maximal therapeutic efficacy. It is further suggested that BRAF mutational status is not predictive of response to MEK inhibition under three-dimensional culture conditions.