The dual PI3K/mTOR-pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases.

Purpose: Previous studies have shown that the PI3K/Akt/mTOR-pathway 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-wildtype breast cancer cell lines and the isogenic pairs of PIK3CA-wildtype and -mutant (H1047R/+) 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 immunohistochemistry. 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-wildtype cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA-wildtype brain tumors. Conclusions: The results of this study suggest that the brain-penetrant 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.

Ippen FM, Alvarez-Breckenridge CA, Kuter BM, Fink AL, Bihun IV, Lastrapes M, Penson T, Schmidt SP, Wojtkiewicz GR, Ning J, Subramanian M, Giobbie-Hurder A, Martinez-Lage M, Carter SL, Cahill DP, Wakimoto H, Brastianos PK.
Clin Cancer Res. 2019 Feb 22. pii: clincanres.3049.2018. doi: 10.1158/1078-0432.CCR-18-3049. [Epub ahead of print]