New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists.

Hetty Carraway,Manuel Hidalgo

doi:10.1186/bcr927

Abstract

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G1 phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy.

Highlights

Mammalian target of rapamycin is a serinethreonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple functions such as transcriptional and translational control
Activation of Mammalian target of rapamycin (mTOR) as a consequence of nutrients and growth factors results in the phosphorylation and activation of the 40S ribosomal protein S6 kinase (p70S6K) and the eukaryotic initiation factor 4E-binding protein-1 (4EBP1; Fig. 1). These proteins play a key role in ribosomal biogenesis and cap-dependent translation, which result in increased translation of mRNAs that are important to the control and progression of the cell cycle. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival
PI3K/Akt and mTOR pathways appear to be critical for the proliferative responses mediated by epidermal growth factor receptor, the insulin-like growth factor (IGF) receptor and the estrogen receptor (ER). These findings suggest that it may be rational to pursue the use of pharmacologic inhibitors of mTOR in treating patients with breast cancers, because these malignancies have evidence of hyperactive PI3K/Akt signaling elements and/or aberrations in tumor suppressor proteins such as PTEN

Summary

Introduction

Mammalian target of rapamycin (mTOR) is a serinethreonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple functions such as transcriptional and translational control. (CCI-779, RAD001, AP23573) are specific mTOR antagonists that are used to target this pathway and block the downstream signaling elements and result in cell cycle arrest in the G1 phase These agents have exhibited impressive growth inhibitory effects against a broad range of human cancers, including breast cancer, in preclinical and early clinical evaluations [8,9]. Development of mammalian target of rapamycin inhibitors for cancer treatment Based on preclinical studies suggesting that inhibition of mTOR has antiproliferative effects in a variety of cancer models, clinical studies were initiated with two rapamycin analogs, namely RAD001 and CCI-779 Preliminary results from these studies indicate that these drugs are well tolerated and have promising anticancer activity [37]. Combinations of mTOR inhibitors and cytotoxic agents are expected

Conclusion

Findings

Smith CL