Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Glia. 2018 Nov;66(11):2438-2455. doi: 10.1002/glia.23485. Epub 2018 Oct 25.
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
乳腺癌细胞中 PI3K 信号通路的突变和激活与脑转移有关。然而，在这里我们描述的是，在一些乳腺癌脑转移样本中，PI3K 信号成分的蛋白表达仅限于转移的微环境。与 PI3K 抑制对乳腺癌细胞的治疗效果相反，大脑微环境的反应还不太清楚。因此，我们旨在定量乳腺癌脑转移中 PI3K 通路的活性，并研究 PI3K 抑制对中枢神经系统 (CNS) 微环境的影响。首先，为了系统地定量乳腺癌脑转移中的 PI3K 通路活性，我们使用反向蛋白质阵列 (RPPA) 进行了一项前瞻性生物标志物研究。在检查的 48 个脑转移组织中，有 30 个（62.5%）显示出高 PI3K 信号活性，与中位总生存期 (OS) 为 9.41 个月相关，而脑转移仅显示中或低 PI3K 活性的患者的中位总生存期分别仅为 1.93 个月和 6.71 个月。其次，我们确定 PI3K 是中枢神经系统定植期间促进转移的巨噬细胞/小胶质细胞的主要调节因子；用 buparlisib（BKM120）治疗，一种血脑屏障通透性良好的 pan-PI3K Class I 抑制剂，可降低其促进转移的特征。总之，PI3K 信号在大多数乳腺癌脑转移中是活跃的。由于 PI3K 抑制不仅影响转移细胞，而且还重新教育促进转移的巨噬细胞/小胶质细胞，因此 PI3K 抑制在治疗脑转移和相应的微环境方面可能具有很大的潜力。
