Reversing Hormone Resistance: Have We Found the Golden Key?

Abstract

Hormone receptors are present in the majority of both early- and late-stage breast cancers, with expression found in approximately 65% to 70% of metastatic tumors. Despite the availability of a number of effective hormone therapies, resistance develops in a subset of earlystage tumors and in almost all tumors in the advanced setting. In addition, a subset of hormone receptor–positive tumors are primarily resistant to hormone therapies. The search for mechanisms to reverse resistance has focused on inhibiting pathways that are known to be upregulated in the setting of progressive disease. 1-3 Improvements in response and progression-free survival (PFS) that were seen with the addition of human epidermal growth factor receptor 2 (HER2)– targeted therapy to first-line aromatase inhibitors in patients with HER2-positive, hormone receptor–positive metastatic breast cancer represented the first clear indication that targeting growth factor receptor pathways could be an effective approach to reversing resistance, 4,5 and added additional validity to preclinical models that predicted this effect. 3 However, only approximately 8% to 10% of breast cancers are both HER2- and hormone receptor–positive, so the search for other approaches remains a critical research and clinical question. Phosphatidyl inositol 3-kinase (PI3K) is the most frequently altered pathway in breast cancer, with both mutations and amplifications of the encoding genes. 6 This pathway mediates a number of critical cellular processes including cell growth, proliferation, and survival. Mammalian target of rapamycin (mTOR) is a signal transduction kinase in the PI3K pathway that exists in two multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and mTORC2; Fig 1). mTORC1 consists of mTOR that is associated with raptor (regulatory-associated protein of mTOR) and is downstream of AKT. In contrast, mTORC2 is associated with rictor (rapamycin-insensitive