Cancer Letters

Cancer Letters

Volume 319, Issue 1, 1 June 2012, Pages 1-7
Cancer Letters

Mini-review
mTOR inhibitors in cancer therapy

https://doi.org/10.1016/j.canlet.2012.01.005Get rights and content

Abstract

The mammalian target of rapamycin (mTOR) plays a key role in regulation of cellular metabolism, growth, and proliferation. The frequent hyperactivation of mTOR signaling makes it an attractive target for therapeutic intervention and has driven the development of a number of mTOR inhibitors. Encouraging data from preclinical studies have resulted in initiation of multiple clinical trials. Furthermore, combinational strategies are being studied in an effort to overcome resistance and enhance efficacy. Although additional studies are required to determine their specific role in the clinical setting, mTOR inhibitors remain a promising therapeutic option for the treatment of cancer.

Introduction

The mammalian target of rapamycin (mTOR) is a highly conserved serine–threonine kinase belonging to the phosphatidylinositol kinase-related protein kinases family [1]. mTOR plays a central role in cellular homeostasis and has been implicated in a number of cellular events including cell growth, survival, and metabolism [2]. A growing body of evidence identifies activation of mTOR signaling as a common occurrence in human cancers [3]. Moreover, mTOR is closely intertwined with the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is strongly linked with neoplastic disease [2]. These factors have made mTOR an attractive option for the development of molecular targeted therapies, many of which have now progressed to clinical trials.

Section snippets

The mTOR signaling pathway

mTOR is a catalytic subunit composed of at least two distinct multi-protein complexes designated mTOR complex 1 (mTORC1) and mTORC2 [2] (Fig. 1). mTORC1 is comprised of mTOR, regulatory-associated protein of mTOR (Raptor), mLST8/GβL, Deptor, and proline-rich Akt substrate 40 [4]. mTORC1 is regulated by diverse environmental signals including nutrients, growth factors, energy signals, and cellular stress [1]. Additionally, the PI3K/Akt pathway is an important upstream mediator of mTORC1, which

The role of mTOR in cancer

In the last few years, significant advances have been made in understanding the role of mTOR in cancer development and progression. Increased mTOR signaling in cancers often occurs as a result of mutations in pathways closely related to mTOR. For example, upregulation of the PI3K/Akt pathway through mutations such as amplification of the PIK3CA gene (encodes the p110α subunit of PI3K) can constitutively activate mTOR signaling [23]. Furthermore, loss or inactivation of phosphatase and tensin

Rapamycin and its derivatives

Rapamycin (sirolimus), a naturally occurring compound isolated from the soil bacterium Streptomyces hydroscopius, was originally used as an antifungal and immunosuppressive agent [23]. Subsequent discovery of mTOR as the target of rapamycin and the drug’s inherent antiproliferative properties led to investigation of this compound as an anti-cancer agent. Limitations in the solubility and pharmacokinetic properties of rapamycin have driven efforts to improve upon these characteristics, resulting

ATP-competitive mTOR kinase inhibitors

Limitations of rapamycin-based therapies in the clinical setting have led to development of a second generation of mTOR inhibitors known as ATP-competitive mTOR kinase inhibitors (TKIs). These inhibitors target the kinase domain of mTOR and inhibit its catalytic activity. The mechanistic advantage of these drugs is that they inhibit the kinase activity of both the TORC1 and TORC2 complexes of mTOR, while also blocking the feedback activation of PI3K/Akt signaling [1], [49]. Numerous TKIs have

Dual mTOR/ PI3K inhibitors

The close interaction of mTOR with the PI3K pathway as well as concerns regarding resistance to TKIs via feedback activation of PI3K/Akt prompted development of dual PI3K/mTOR inhibitors. Recently developed dual PI3K/mTOR inhibitors include NVP-BEZ235, BGT226, XL765/SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458. These inhibitors target the p110α, β, and γ isoforms of PI3K as well as the ATP-binding sites of both mTORC1 and mTORC2, completely suppressing PI3K/Akt

Combinational strategies with mTOR inhibitors

Although a number of cancers respond to monotherapy treatment with rapalogs, TKIs, and dual PI3K/mTOR, resistance remains a major concern [43]. Combination therapeutic strategies may provide a way to overcome this resistance and improve efficacy of mTOR targeting agents. Rapalogs have been tested in combination with standard chemotherapy, receptor tyrosine kinase targeted therapies, and angiogenesis inhibitors [23]. For example, a recent study of epitheloid sarcoma demonstrated that the

Future perspectives

Given the limitations of currently available inhibitors, new approaches to mTOR targeting are under investigation. One possible strategy is to selectively inhibit mTORC2. Selective inhibition of mTORC2 would eliminate activation of PI3K through the S6K1-insulin receptor substrate 1 feedback loop [1]. Furthermore, the increased toxicity seen in TKIs as a result of concomitant mTORC1 inhibition may be avoided. Another potential strategy is to target DEP domain-containing mTOR-interacting protein

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