Abstract P4-07-01: The Class I Selective PI3K Inhibitor GDC-0941 Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing the Rate of Apoptosis

Docetaxel (DTX) is commonly used as a front-line treatment option for breast cancer but many patients ultimately relapse and succumb to disease progression. Phosphatidylinositol 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration and survival. Given that phosphatidylinositol 3-kinase (PI3K) is frequently activated in breast cancer and induces chemo-resistance, it is an attractive target for combination therapy with standard of care drugs such as DTX. 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. A panel of 25 breast tumor cell lines representing luminal, HER2+ and basal sub-types 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. The combination of GDC-0941 and DTX decreased the cellular viability of breast tumor cell lines in vitro but with variable drug synergy. The addition of both drugs resulted in stronger synergistic effects in a sub-set of tumor cell lines that was not predicted by breast cancer sub-type or mutations within the PI3K pathway. Human xenografts of breast cancer cell lines and patient-derived tumors were utilized to assess efficacy of GDC-0941 and DTX in vivo. In these models, the best combination efficacy was detected when the two drugs were dosed within 1 hour of each other. We also observed that GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon co-treatment with DTX. Our data provides a preclinical rationale for evaluating GDC-0941 in combination with DTX for breast cancer treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-01.