Associate editor: B. Teicher
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway

https://doi.org/10.1016/j.pharmthera.2013.12.004Get rights and content

Abstract

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

Introduction

The mechanisms underlying cancer are marked by complex aberrations that activate critical cellular signaling pathways in tumorigenesis. The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling cascade is one of the most important intracellular pathways, which is frequently activated in diverse cancers (Fig. 1) (Liu et al., 2009, Janku, Wheler, Naing, et al., 2012). PI3K/AKT/mTOR signaling regulates cell proliferation, differentiation, cellular metabolism, and cytoskeletal reorganization leading to apoptosis and cancer cell survival. Activation of the PI3K/AKT/mTOR signaling pathway mediated through molecular aberrations is instrumental in promoting tumor development as well as resistance to anticancer therapies (Engelman, 2009, Burris, 2013). In addition, germline mutations in PI3K/AKT/mTOR signaling can cause hereditary disorders associated with a high incidence of cancers. Examples include Cowden's disease associated with loss-of-function of the phosphatase and tensin homolog (PTEN) gene (Aslam & Coulson, 2013), tuberous sclerosis complex caused by a mutation in either of the tuberous sclerosis complex 1/2 (TSC1 and TSC2) genes (Kohrman, 2012), and Peutz–Jeghers syndrome, which is linked to a mutation in the LKB1 gene (also known as STK11) (Kuwada & Burt, 2011).

Numerous efforts have been made to develop PI3K/AKT/mTOR targeted therapies for cancer treatment. Various drugs such as PI3K, AKT, or mTOR kinase inhibitors are in clinical development and allosteric inhibitors of mTOR complex 1 (mTORC1), temsirolimus and everolimus, have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating advanced renal cell cancer (Hudes et al., 2007, Motzer et al., 2008), hormone receptor-positive, HER2-negative breast cancer in combination with hormonal therapy (Baselga et al., 2012), and neuroendocrine tumors of pancreatic origin (Table 1) (Yao et al., 2011). However, these drugs have limited efficacy as single agents. Molecular factors underlying response to them and optimal drug combinations that can act against therapeutic resistance have yet to be identified.

This review delineates the PI3K/AKT/mTOR signaling cascade and emerging molecular targets for targeted therapy in cancer.

Section snippets

The biology of the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin pathway

The PI3K/AKT/mTOR pathway can be activated by transmembrane tyrosine kinase growth factor receptors, such as ErbB family receptors, fibroblast growth factor receptors (FGFR), insulin-like growth factor 1 receptor (IGF-1R), and others (Knuefermann et al., 2003, Stern, 2008). In addition, G protein-coupled receptors such as activated RAS (Stephens et al., 1997, Zhao and Vogt, 2008a) can stimulate PI3K through its catalytic subunit (Fig. 1) (Stephens et al., 1997, Shaw and Cantley, 2006, Zhao and

Molecular targets in phosphatidylinositol 3-kinase

Most cancers driven by PI3K/AKT/mTOR signaling aberrations are marked by PI3K kinase mutations. The PI3K protein family comprises at least three different lipid kinase classes (class I, II and III). Class I PI3K contains four different isoforms, catalytic domains p110α (PIK3CA), p110β (PIK3CB), p110γ (PIK3CG) and p110δ (PIK3CD). The roles of class II PI3K, PI3K‑C2α (PIK3C2A), PI3K‑C2β (PIK3C2B) and PI3K‑C2γ (PIK3C2G), are ill defined in signal transduction and are generally not involved in

Phosphatase and tensin homolog alterations in cancer

The tumor suppressor gene PTEN (also known as MMAC, mutated in multiple advanced cancers) was initially observed independently by two groups in 1997 on the 10q23 chromosomal region of PTEN, which was known to be deleted in many advanced cancers (Li et al., 1997, Steck et al., 1997). PTEN is a lipid phosphatase that catalyzes the conversion of the second messenger PIP3 to PIP2 and thus reverses PI3K functionality in signal propagation (Fig. 1) (Maehama & Dixon, 1998). Moreover, it is now well

Molecular targets in protein kinase-B

AKT/PKB (protein kinase-B) is a family composed of three serine/threonine kinases known as AKT1, AKT2 and AKT3 (Fig. 1). These isoforms are products of three different genes, but with more than 80% structural homology. AKT is an important part of PI3K signaling as the activation of the protein is caused by PI3K and PDK1 mediated phosphorylation in the catalytic domain at threonine 308 (Alessi et al., 1997, Andjelković et al., 1997). AKT activation is involved in tumor progression through

Tuberous sclerosis complex 1/2 and liver kinase B1 alterations in cancer

The activation of mTOR in the PI3K signaling pathway is inhibited by the complex of two proteins, hamartin and tuberin, (TSC1/TSC2 complex), which are products of the tumor suppressor genes TSC1 and TSC2 (chromosomes 9q34 and 16p13.3, respectively) (European Chromosome 16 Tuberous Sclerosis Consortium, 1993, Van Slegtenhorst et al., 1997). In its steady state, the TSC1/TSC2 complex inactivates RHEB. When the PI3K pathway is activated, the upstream kinase AKT phosphorylates TSC2, which inhibits

Mammalian target of rapamycin alterations in cancer

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, which acts downstream of the PI3K pathway. It is composed of two distinct protein complexes, mTORC1 and mTORC2, that act on different levels of the pathway. mTORC1 consists of mTOR and other associated proteins such as raptor, mLST8, PRAS40 and DEPTOR (Shaw and Cantley, 2006, Guertin and Sabatini, 2007). The mTORC1 complex functions as a key regulator of cellular growth and protein synthesis. This

Conclusion

The aberrant activation of the PI3K/AKT/mTOR pathway on various levels of signaling is frequently observed in many different human malignancies. In addition to sporadic tumor development are hereditary cancer syndromes caused by hyperactive PI3K signaling, such as Cowden's disease, tuberous sclerosis complex, Peutz–Jeghers syndrome, and others. The development of novel inhibitors that could interact with distinct members of this pathway is sorely needed. To date, only a few PI3K-targeted drugs

Financial support

This study is supported by MH CZ —DRO (Faculty Hospital Plzen—FNPl, 00669806) and the project ED2.1.00/03.0076 from the European Regional Development Fund.

Conflict of interest

Filip Janku received research support from Novartis, Roche, Biocartis, Transgenomic, and Trovagene.

Acknowledgments

We thank Ms. Joann Aaron for scientific review and editing of this article.

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