Mammalian target of rapamycin as a rational therapeutic target for breast cancer treatment.

Therapies directed at endocrine receptors and human epidermal growth factor receptor 2 are important treatment options for patients with breast cancer; however, drug resistance and subsequent disease progression in patients with advanced disease is inevitable. The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation implicated in the cellular processes that lead to the uncontrolled growth of cancer cells. Hence, overactivation of the mTOR pathway may also represent a key process in the development of resistance to these therapies, and interrupting this signaling cascade may alleviate resistance and help restore drug sensitivity. A number of agents that target the mTOR pathway have shown potent antitumorigenic effects in vitro, and several agents have also shown promise in treating patients with breast cancer. Everolimus and temsirolimus are the most clinically advanced agents in this class, with recent data from the BOLERO-2 study indicating significant benefit associated with everolimus when added to endocrine therapy in patients with endocrine therapy-resistant disease. In this review, we consider the translation of mTOR inhibitors from laboratory studies to large clinical trials, driven by a rational understanding of the role of mTOR in the processes that underlie breast cancer tumorigenesis.