PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo
PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo
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DOI：
10.1158/1078-0432.ccr-16-0064
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发表时间：
2016-12-01
影响因子：
11.5
通讯作者：
Meier, Friedegund
中科院分区：
文献类型：
--
作者：
Niessner, Heike;Schmitz, Jennifer;Meier, Friedegund
目的：最近在治疗转移性黑色素瘤患者方面取得了巨大进展。然而，现有疗法对脑转移的效果不如脑外转移有效。这凸显了大脑环境对肿瘤进展和耐药性的潜在作用，并强调了“大脑特异性”疗法的必要性。我们之前表明，PI3K-AKT 存活通路在大脑中过度激活，但在脑外黑色素瘤转移中并未过度激活，并且星形胶质细胞条件培养基在体外激活黑色素瘤细胞中的 AKT。因此，我们测试了 PI3K 抑制剂 buparlisib 作为黑色素瘤脑转移的抗肿瘤药物。实验设计和结果：Buparlisib 抑制转移性黑色素瘤细胞系和短期脑黑色素瘤细胞中的 AKT 活性、减少增殖并诱导细胞凋亡，无论其 BRAF 和 NRAS 突变状态如何。此外，buparlisib 还可抑制星形胶质细胞条件培养基刺激的黑色素瘤细胞中过度激活的 AKT 并诱导细胞凋亡。将人 BRAF 和 NRAS 突变的转移性黑色素瘤细胞注射到小鼠大脑中诱导的肿瘤生长被 Buparlisib 显着抑制。结论：这些结果强调了以 PI3K 通路为靶点作为开发黑色素瘤脑转移药物策略的价值。 (C) 2016 年 AACR。
Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. (C) 2016 AACR.