Inhibition of phosphoinositide 3-kinase enhances the cytotoxicity of AG1478, an epidermal growth factor receptor inhibitor, in breast cancer cells.

Aberrant activation and dysfunction of the EGFR/PI3K/Akt signaling pathways are commonly reported in breast cancer. Constitutive activation of the PI3K/Akt pathway by the lack of PTEN regulation is associated with resistance to novel targeted therapies including EGFR inhibitors. We aimed to study whether Ly294002, an inhibitor of PI3K, could enhance the cytotoxicity of AG1478, an inhibitor of EGFR, on breast cancer cells. We tested these agents in the MDA-MB-468 and MCF-7 breast cancer cell lines with different EGFR and PTEN profiles (MDA-MB-468: high expression of EGFR and PTEN mutation; MCF-7: low expression of EGFR and PTEN wild type). Simultaneous inhibition of EGFR and PI3K in MDA-MB-468 cells with combined Ly294002 and AG1478 treatment had a greater anti-proliferative effect and increased mitotic death than either treatment alone. In addition, more apoptosis and increased induction of cell arrest at G0/G1 phase were observed in MDA-MB-468 cells with the combined treatment. Phosphor-EGFR and its downstream signal transducer, phosphor-Akt, were fully attenuated only by simultaneous treatment with Ly294002 and AG1478. These data suggest that the inhibition of PI3K could enhance the cytotoxicity of EGFR inhibitors on breast cancer cells and tumors which overexpress EGFR and demonstrate mutated PTEN. This dual inhibition treatment protocol may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN.