Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer

Abstract

Approximately 70-75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key intracellular signaling system that drives cellular growth and survival; hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer and in resistance to endocrine therapy. Moreover, preclinical and clinical evidence show that PI3K/AKT/mTOR pathway inhibition can augment the benefit of endocrine therapy in ER+ breast cancer, from the first-line setting and beyond. This article will review the fundamental role of the PI3K/AKT/mTOR pathway in driving ER+ breast tumors, and its inherent interdependence with ER signaling. In addition, ongoing strategies to combine PI3K/AKT/mTOR pathway inhibitors with endocrine therapy for improved clinical outcomes, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway, will be evaluated.

Keywords: AKT; Breast cancer; Endocrine resistance; Endocrine therapy; Estrogen receptor; Luminal type; Mammalian target of rapamycin; PI3K; Phosphatidylinositol 3-kinase; mTOR.