Overcoming endocrine resistance in breast cancer: role of the PI3K and the mTOR pathways

Overcoming endocrine resistance is a 21st century hurdle in the treatment of hormone receptor-positive breast cancers. Estrogen plays a role in the growth of 70% of breast cancers. There are many strategies evolved to overcome estrogen resistance. Established strategies include using drugs such as tamoxifen, a selective estrogen receptor modulator to selectively block estrogen receptors and aromatase inhibitors to decrease the synthesis of estrogen. However, endocrine resistance is commonly encountered in treating patients with standard single-therapy regimens. Recently, the role of the PI3K and the mTOR pathways has been targeted to overcome resistance. The mTOR pathway is a complex pathway regulating cell metabolism, growth and apoptosis. Novel agents such as mTOR inhibitors, PI3K inhibitors and Akt inhibitors are transitioning from bench-top research to clinical application with promising results. This article reviews the common mechanisms of endocrine resistance, and combination therapies that utilize the mTOR/PI3K pathways to overcome resistance.