GDC-0941, A Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo
Menée sur des lignées cellulaires de cancer du sein et à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé GDC-0941, un inhibiteur sélectif de PI3K par voie orale, à augmenter l'activité antitumorale du docétaxel
Purpose: Docetaxel (DTX) is a front-line standard of care chemotherapeutic drug for the treatment of breast cancer. Phosphatidylinositol 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration and survival. The current study was intended to determine if GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the anti-tumor activity of DTX in human breast cancer models in vitro and in vivo. Experimental Design: A panel of 25 breast tumor cell lines representing HER2+, luminal and basal subtypes were treated with GDC-0941, DTX or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers and apoptosis induction. Drug combination effects on cellular viability were also assessed in non-transformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were utilized to assess efficacy of GDC-0941 and DTX in vivo. Results: Combination of GDC-0941 and DTX decreased the cellular viability of breast tumor cell lines in vitro but to variable degrees of drug synergy. Compared to non-transformed MCF10A cells, the addition of both drugs resulted in stronger synergistic effects in a sub-set of tumor cell lines that were not predicted by breast cancer subtype. In xenograft models, GDC-0941 enhanced the anti-tumor activity of DTX with maximum combination efficacy observed within 1 hour of administering both drugs. GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon co-treatment with DTX. Conclusions: GDC-0941 augments the efficacy of DTX by increasing drug-induced apoptosis in breast cancer models.