Targeting the PI3K/Akt/mTOR-pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases


Activating mutations in the PI3K/AKT/mTOR-pathway occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt-inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model.


In in vitro studies, antitumor activity of GDC-0068 was assessed in PIK3CA-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis and Western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry.


GDC-0068 decreased cell viability, induced apoptosis and inhibited phosphorylation of PRAS40 and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared to PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared to sham whereas no effect was detected in a PIK3CA-wildtype model.


This study suggests that the Akt-inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.

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S2808 Ipatasertib (GDC-0068) Ipatasertib (GDC-0068, RG7440) is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM in cell-free assays, 620-fold selectivity over PKA. Phase 2. (82) (3)

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