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 wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type 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 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 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.
Bibliographical noteFunding Information:
F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation- Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer Research Foundation, Susan G. Komen, American Brain Tumor Association, and NIH (R01 CA227156).
F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation-Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer ResearchFoundation, SusanG.Komen, American BrainTumor Association,and NIH (R01 CA227156).
© 2019 American Association for Cancer Research.