The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases
The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases
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DOI：
10.1158/1078-0432.ccr-18-3049
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发表时间：
2019-06-01
影响因子：
11.5
通讯作者：
Brastianos, Priscilla K.
中科院分区：
文献类型：
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作者：
Ippen, Franziska M.;Alvarez-Breckenridge, Christopher A.;Brastianos, Priscilla K.
目的：以前的研究表明，PI 3 K/Akt/mTOR通路在高达70%的乳腺癌脑转移中被激活，但没有批准的药物用于受影响的患者。GDC-0084是一种脑渗透剂，双重PI 3 K/mTOR抑制剂，在胶质母细胞瘤的临床前模型中显示出有希望的活性。实验设计：在体外PIK 3CA突变型和PIK 3CA野生型乳腺癌细胞系以及PIK 3CA野生型和突变型（H1047 R/thorn）MCF 10A细胞的同基因对中评估GDC-0084的功效。体外研究包括细胞活力和凋亡测定、细胞周期分析和蛋白质印迹。在体内，GDC-0084的效果进行了研究，在乳腺癌脑转移异种移植物小鼠模型和评估通过生物发光成像和IHC.Results：在体外，GDC-0084显着降低细胞活力，诱导凋亡，并抑制Akt和p70 S6激酶的磷酸化，在PIK 3CA突变的乳腺癌脑转移细胞系中以剂量依赖性的方式。相比之下，GDC-0084在体外仅导致PIK 3CA野生型细胞系的生长抑制。在体内，治疗与GDC-0084显着抑制PIK 3CA突变体的生长，伴随着信号的变化，而不是PIK 3CA野生型brain-tumors.Conclusions：本研究的结果表明，脑渗透剂PI 3 K/mTOR靶向GDC-0084是一个有前途的治疗选择乳腺癌脑转移与失调的PI 3 K/mTOR信号通路赋予激活PIK 3CA突变。计划进行一项国家临床试验，以进一步研究这种化合物在脑转移患者中的作用。
Purpose: Previous studies have shown that the PI3K/Akt/ mTORpathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/thorn) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.Results: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors.Conclusions: The results of this study suggest that the brainpenetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.