Abstract
Breast cancer is the second most common primary tumor leading to brain metastases in adult cancer patients. Previous studies have shown that the PI3K/AKT/mTOR pathway in breast cancer brain metastasis is activated in up to 70% of analyzed tumors. However, there are no approved agents targeting this pathway in breast cancer brain metastases at present. GDC-0084 is a dual brain penetrant PI3K/mTOR-inhibitor that has already demonstrated promising response rates in a preclinical glioblastoma model. The aim of this study was to analyze the efficacy of this compound in a breast cancer brain metastases model in vitro and in vivo using PIK3CA-mutant and PIK3CA-wildtype cell lines. In vitro methods included cell viability, apoptosis, growth inhibition assays, cell cycle analysis, Western blots and immunohistochemistry. In vivo, the effect of GDC-0084 was evaluated in an orthotopic intracranial mouse model with bioluminescent imaging. GDC-0084 induced apoptosis in PIK3CA-mutant breast cancer brain metastases cell lines and growth inhibition in PIK3CA-wildtype cell lines in vitro and markedly inhibited tumor growth of PIK3CA-mutant cell lines in vivo. The results of this study highlight the importance of brain-penetrant agents targeting the PI3K/AKT/mTOR-pathway and suggest that GDC-0084 might be a promising treatment option for breast cancer brain metastases patients in the future.