Clinical development of mTOR inhibitors in breast cancer

Abstract

The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians.

Figure 1

mTOR pathway and actions. Schematic representation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. mTOR complex (mTORC)1 is involved in mRNA translation and protein synthesis, glucose metabolism, lipid synthesis, and estrogen receptor (ER) phosphorylation and inhibits autophagy. mTORC2 functions in AKT phosphorylation on serine 473 and regulates the cellular actin cytoskeleton. 4E-BP1, eIF4E binding protein 1; AMPK, adenosine monophosphate-activated protein kinase; E, Estrogen; LKB1, liver kinase B1; MEK, mitogen activated protein kinase/extracellular signal regulated kinase; P, phosphorylated; raf, rat fibrosarcoma virus; Ras, rat sarcoma virus; S6K1, ribosomal protein S6 kinase; TSC1/2, tuberous sclerosis 1/2.

Figure 2

mTOR-dependent pathways and inhibitors. Mammalian target of rapamycin (mTOR) depends on two pathways: the phosphatidylinositol-3-kinase (PI3K)-dependent pathway and the 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway (the energy pathway). Various inhibitors have been reported to act on one kinase in each of the pathways. LKB1, liver kinase B1; mTORC, mTOR complex; TSC1/2, tuberous sclerosis 1/2.

Figure 3

Everolimus sensitivity. Schematic representation of the sensitivity to everolimus. 4E-BP1, eIF4E binding protein 1; AKT, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; IGF1R, insulin growth factor 1-receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycine; PI3K, phosphatidylinositol-3-kinase.

Figure 4

Feedback loops after rapalog exposure. After rapamycin, various feedback loops are triggered by ribosomal protein S6 kinase beta-1 (S6K1). The S6K1/insulin-like growth factor 1 receptor (IGF-1R)/phosphatidylinositol-3-kinase (PI3K) loop results in protein kinase B (AKT) activation, while the second loop is S6K1/IGF-IR/PI3K and mitogen-activated protein kinase (MAPK) pathway-dependent. Both loops are implicated in secondary resistance to mammalian target of rapamycin (mTOR) inhibitors. mTORC, mTOR complex; P, phosphorylated; Ras, rat sarcoma virus; TK, tyrosine kinase.