Mammalian Target of Rapamycin: Biological Function and Target for Novel Anticancer Agents

Emily B. Borders, Pharm.D., BCOP; Cory Bivona; Patrick J. Medina, Pharm.D., BCOP

Am J Health Syst Pharm. 2010;67(24):2095-2106.

Abstract and Introduction

Abstract

Purpose. The biological function of the mammalian target of rapamycin (mTOR) and mechanisms of action of mTOR inhibitors currently available for clinical use are described.
Summary. mTOR is a target for anticancer agents due to its role in cancer development, progression, and resistance to other antineoplastic agents. Currently, two mTOR inhibitors, temsirolimus and everolimus, are approved for the treatment of patients with advanced renal cell carcinoma (RCC). Clinical trials comparing single-agent temsirolimus with interferon alfa-2a demonstrated an improvement in overall survival and progression-free survival (PFS) in patients with metastatic RCC. Clinical studies comparing everolimus with placebo indicated improved PFS in advanced RCC patients whose disease had progressed on or after vascular endothelial growth factor (VEGF) inhibitor therapy. Due to its role in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, mTOR is a rational target for inhibition in combination with other agents, including traditional chemotherapy and agents that are affected by or target the PI3K pathway. Data from these studies review the use of mTOR inhibitors in non-Hodgkin's lymphoma and endometrial, breast, and neuroendocrine tumors. Common toxicities of mTOR inhibitors include mucositis, stomatitis, rash, asthenia, fatigue, and myelosuppression. Additional toxicities requiring monitoring include hyperglycemia, hyperlipidemia, and pneumonitis.
Conclusion. The mTOR signaling pathway is upregulated in a variety of solid and hematologic tumors. Two inhibitors of this pathway, temsirolimus and everolimus, have been approved for use in metastatic RCC. Although relatively safe, these drugs are associated with some unique adverse effects, such as hyperlipidemia, hyperglycemia, and pneumonitis, that require monitoring and may require clinical intervention.

Introduction

The approval of rituximab in 1997 for non-Hodgkin's lymphoma ushered in the era of antineoplastic agents as "targeted" agents. These agents are designed to target the underlying tumor biology or specific characteristics present on the majority of cancer cells. To date, the majority of these agents target either extracellular cell surface receptors or intracellular receptor tyrosine kinases. However, many tumors do not respond to these agents. Several reasons have been hypothesized for this lack of response, including the presence of tumor mutations that bypass upstream intracellular signals, allowing signal transduction to occur in the absence of cell surface receptor activation. Activation of downstream signaling kinases is a complex process that may be accomplished by more than one pathway. Therefore, when an antineoplastic agent blocks one upstream signaling pathway (e.g., trastuzumab's inhibition of ERBB2 [formerly HER2/neu]), alternative signaling pathways are activated, allowing signal transduction to occur despite the use of one antineoplastic agent.^[1] Increased emphasis on predicting which patients will benefit most from these agents is an area of intense clinical interest.

New agents are being designed that target downstream signal transduction. By working further along the signal transduction pathway, these agents are designed to potentially block more than one signaling pathway involved in cancer development and progression. The mammalian target of rapamycin (mTOR) is one such downstream kinase involved in cancer development, progression, and resistance to antineoplastic agents. The mTOR pathway was discovered in the early 1990s during investigations into rapamycin's mechanism of action as an antifungal and immunosuppressive agent. Rapamycin is a macrolide ester first isolated from the bacterium Streptomyces hygroscopicus.^[2] Rapamycin is marketed in the United States as sirolimus; the labeling for sirolimus was approved for prevention of organ rejection in patients receiving renal transplants.^[2] Rapamycin inhibits T-lymphocyte activation and proliferation that occur in response to antigenic and cytokine stimulation. Subsequent data have demonstrated that rapamycin has antiproliferative effects on human tumor cells. The binding protein of rapamycin leading to these effects was named target of rapamycin and later mTOR to reflect its role in mammalian cell proliferation and growth.

Recently, a new class of antineoplastic agents—mTOR inhibitors—have been developed and introduced as antitumor agents based on these antiproliferative effects. Currently, two mTOR inhibitors are approved for the treatment of metastatic renal cell carcinoma (RCC), temsirolimus and everolimus, and many others are being studied in clinical trials. This article describes the biological function of mTOR (including its role in cancer development and progression), the mechanism of action of mTOR inhibitors, and the two mTOR inhibitors that are currently available for clinical use in the United States.

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Table 1. Select Members of the Mammalian Target of Rapamycin (mTOR) Signaling Network^a
Protein (Abbreviation)	Location in Relation to mTOR	Comments
Akt family of proteins (Akt)	Upstream of mTORC1 and downstream of mTORC2	Requires phosphorylation by PI3K as well as mTORC2 for activity, phosphorylates many proteins involved in cell survival, downregulates TSC2 and PRAS40, leading to increased mTORC1 activity
AMP-activated protein kinase (AMPK)	Upstream of mTORC1	Activates TSC2 in response to low energy levels and decreases mTORC1 activity, responds to low energy levels by decreasing mTORC1 activation and subsequent cell growth and proliferation
Human epidermal growth factor receptor-2 (ERBB2)	Upstream of mTORC1	Encompasses a group of growth factors, including EGFR and ERBB2, known to be overexpressed in many cancers; similar function as IRS-1, though it may not be affected by S6K1 activity
Eukaryotic translation initiation factor 4E (eIF4E)	Downstream of mTORC1	Allows for transcription of several growth factors, including cyclin D1 and VEGF
Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)	Downstream of mTORC1	Activated by mTORC1 and then dissociates from eIF4E; elevated phosphorylated levels seen in some cancers
Insulin receptor substrate-1 (IRS-1)	Upstream of mTORC1	Activates PI3K pathway starting downstream signal transduction of Akt, may be increased with mTORC1 inhibition due to loss of S6K1 negative feedback
Phosphatase and tensin homologue (PTEN)	Upstream of mTORC1	Tumor-suppressor gene that negatively regulates and antagonizes PI3K effects; loss of or mutated PTEN is demonstrated in many tumor types
Phosphatidylinositol 3-kinase (PI3K)	Upstream of mTORC1	Upregulated in many cancers; involved in cell survival, proliferation, and differentiation
Proline-rich Akt substrate 40 kDa (PRAS40)	Part of mTORC1 complex	Inhibits mTORC1 activity
Ribosomal protein S6 kinase 1 (S6K1)	Downstream of mTORC1	Phosphorylates ribosomal protein S6 (and other proteins) to allow for translation of elongation factors involved in protein synthesis, decreases activation of PI3K pathway by degrading IRS-1
Tuberous sclerosis complex 2 (TSC2)	Upstream of mTORC1	Negatively regulates mTORC1 activity with TSC1 by modulating proteins that activate mTORC1; inactivating phosphorylations of TSC2 (and increased mTORC1 activity) occur from Akt in response to growth factor stimulation

^amTORC1 = mTOR complex 1, mTORC2 = mTOR complex 2, EGFR = epidermal growth factor receptor, VEGF = vascular endothelial growth factor, TSC1 = tuberous sclerosis complex 1.

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