Haass Nikolas K, Sproesser Katrin, Nguyen Thiennga K, Contractor Rooha, Medina C Angelica, Nathanson Katherine L, Herlyn Meenhard, Smalley Keiran S M
The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Clin Cancer Res. 2008 Jan 1;14(1):230-9. doi: 10.1158/1078-0432.CCR-07-1440.
Disseminated melanoma is highly therapy resistant. The finding that 66% of melanomas harbor the activating BRAF(V600E) mutation has raised expectations for targeting the Ras/RAF/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway in melanoma. This study addresses the anti-melanoma activity of the MEK inhibitor AZD6244 (ARRY-142886).
We recently have shown that growing melanoma cells as three-dimensional collagen-implanted spheroids enhances resistance to the MEK inhibitor U0126. Here, we investigated the anti-melanoma activity of AZD6244 in two-dimensional cell culture, the three-dimensional spheroid model, and an in vivo model.
In two-dimensional cell culture, AZD6244 was cytostatic and reduced the growth of melanoma cells in a concentration-dependent fashion through the induction of G(1)-phase cell cycle arrest. In our three-dimensional spheroid model, the effects of AZD6244 were largely cytostatic and reversible, with drug washout leading to spheroid regrowth. Finally, 1205Lu cells were grown as tumor xenografts in severe combined immunodeficient mice. After tumor establishment, mice were dosed twice daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased phospho-ERK in the tumors and significantly suppressed tumor growth. The original tumors remained viable, suggesting that AZD6244 monotherapy was largely cytostatic, and not proapoptotic in this model. Further studies showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15 mg/kg) led to tumor regression, indicating the potential for MEK inhibitor/chemotherapy drug combinations.
Inhibition of MEK is cytostatic as a monotherapy in melanoma, but cytotoxic when combined with docetaxel.
播散性黑色素瘤对治疗具有高度抗性。66%的黑色素瘤携带激活型BRAF（V600E）突变这一发现，提高了人们针对黑色素瘤中Ras/RAF/丝裂原活化蛋白（MAP）/细胞外信号调节激酶（ERK）激酶（MEK）/ERK通路进行靶向治疗的期望。本研究探讨了MEK抑制剂AZD6244（ARRY - 142886）的抗黑色素瘤活性。
我们最近发现，将黑色素瘤细胞培养成三维胶原植入球体可增强对MEK抑制剂U0126的抗性。在此，我们研究了AZD6244在二维细胞培养、三维球体模型及体内模型中的抗黑色素瘤活性。
在二维细胞培养中，AZD6244具有细胞生长抑制作用，并通过诱导G1期细胞周期停滞以浓度依赖方式降低黑色素瘤细胞的生长。在我们的三维球体模型中，AZD6244的作用主要是细胞生长抑制且可逆，药物洗脱后球体重新生长。最后，将1205Lu细胞作为肿瘤异种移植物接种于严重联合免疫缺陷小鼠体内。肿瘤形成后，小鼠每天口服给予0、10或30 mg/kg AZD6244两次。AZD6244治疗降低了肿瘤中的磷酸化ERK水平，并显著抑制肿瘤生长。原始肿瘤仍然存活，表明在该模型中AZD6244单药治疗主要是细胞生长抑制作用，而非促凋亡作用。进一步研究表明，AZD6244（30 mg/kg）与多西他赛（15 mg/kg）联合给药导致肿瘤消退，表明MEK抑制剂/化疗药物联合使用具有潜力。
在黑色素瘤中，MEK抑制作为单药治疗具有细胞生长抑制作用，但与多西他赛联合时具有细胞毒性。
