The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in <i>PIK3CA</i>-Mutant Breast Cancer Brain Metastases.

Abstract

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.<b>Experimental Design:</b> The efficacy of GDC-0084 was evaluated in <i>PIK3CA</i>-mutant and <i>PIK3CA</i> wild-type breast cancer cell lines and the isogenic pairs of <i>PIK3CA</i> wild-type and mutant (H1047R/+) MCF10A cells <i>in vitro</i>. <i>In vitro</i> studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. <i>In vivo</i>, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. <i>In vitro</i>, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in <i>PIK3CA</i>-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in <i>PIK3CA</i> wild-type cell lines <i>in vitro</i>. <i>In vivo</i>, treatment with GDC-0084 markedly inhibited the growth of <i>PIK3CA</i>-mutant, with accompanying signaling changes, and not <i>PIK3CA</i> wild-type brain tumors. 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 <i>PIK3CA</i> mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.