Activation of AKT Kinases in Cancer: Implications for Therapeutic Targeting

The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3‐kinase. An ever‐increasing list of AKT substrates has precisely defined the multiple functions of this kinase family in normal physiology and disease states. Cellular processes regulated by AKT include cell proliferation and survival, cell size and response to nutrient availability, intermediary metabolism, angiogenesis, and tissue invasion. All these processes represent hallmarks of cancer, and a burgeoning literature has defined the importance of AKT alterations in human cancer and experimental models of tumorigenesis, continuing the legacy represented by the original identification of v‐Akt as the transforming oncogene of a murine retrovirus. Many oncoproteins and tumor suppressors intersect in the AKT pathway, finely regulating cellular functions at the interface of signal transduction and classical metabolic regulation. This careful balance is altered in human cancer by a variety of activating and inactivating mechanisms that target both AKT and interrelated proteins. Reprogramming of this altered circuitry by pharmacologic modulation of the AKT pathway represents a powerful strategy for rational cancer therapy. In this review, we summarize a large body of data, from many types of cancer, indicating that AKT activation is one of the most common molecular alterations in human malignancy. We also review mechanisms of activation of AKT kinases, examples of therapeutic modulation of the AKT pathway in animal models, and the current status of efforts to target molecular components of the AKT pathway for cancer therapy and, possibly, cancer prevention.

Introduction

During the past decade, the field of cancer biology has witnessed an enormous upsurge of research activity concerning the AKT kinases, their role in tumorigenesis, and the possibility of targeting them therapeutically and/or as a chemoprevention strategy. The three AKT kinases are now known to represent central nodes in a variety of signaling cascades that regulate normal cellular process such as cell size/growth, proliferation, survival, glucose metabolism, genome stability, and neo‐vascularization (reviewed in Bellacosa et al., 2004). In recent years, however, a burgeoning literature attests to the frequent hyperactivation of AKT kinases in a broad array of human solid tumors and hematological malignancies (reviewed in Cantley 2002, Testa 2001), and a series of elegant studies using animal models has demonstrated that aberrant signaling involving the AKT pathway can, either alone or by cooperating with certain other genetic perturbations, induce malignancy or contribute to a more malignant phenotype (reviewed in Bellacosa 2004, Bjornsti 2004, Di Cristofano 2000, Luo 2003).

It is now evident that AKT is a central player in a signaling pathway of which many components, including the upstream phosphatidylinositol 3‐kinase (PI3K) (Philp 2001, Samuels 2004, Shayesteh 1999), PTEN (phosphatase and tensin homologue deleted on chromosome ten) (reviewed in Cantley 1999, Di Cristofano 2000), and LKB1 (Boudeau et al., 2003), and the downstream tuberous sclerosis complex 2 (TSC2) (reviewed in Kwiatkowski 2003, Manning 2003) and eukaryotic initiation factor 4E (eIF4E) (Avdulov 2004, Bjornsti 2004, Mamane 2004, Ruggero 2004, Wendel 2004), have been linked to tumorigenesis. Some of these proteins, such as the p110α catalytic and p85α regulatory subunits of PI3K, AKT, and eIF4E, are encoded by (proto)oncogenes, whereas others (PTEN, LKB1, and TSC2) are tumor suppressor gene products. Interestingly, in addition to sporadic genetic changes of these genes in many common human cancers, germ line mutations in PTEN, LKB1, and TSC2 result in three distinct, dominantly inherited cancer syndromes characterized by multiple hamartomas and predisposition to certain malignancies (reviewed in Boudeau 2003, Eng 2003, Kwiatkowski 2003). Collectively, these signaling proteins are components of a PI3K‐AKT‐mTOR (mammalian target of rapamycin) axis that, when deregulated, leads to disruptions in the translation of various cancer‐related mRNAs that are involved in such processes as cell cycle progression, autocrine growth stimulation, cell survival, invasion, and communication with the extracellular environment (Mamane et al., 2004).

Because the AKT signaling cascade is frequently disrupted in many human cancers, and in light of the wide‐ranging biologic consequences described above, this pathway is considered a key determinant of tumor aggressiveness and an attractive target for therapeutic intervention (Mitsiades et al., 2004). On the other hand, the fact that AKT signaling affects many important downstream pathways, such as glucose metabolism, means that the potential liabilities of such a molecularly targeted approach must be carefully addressed.

The biochemical mechanisms involved in AKT kinase activation have been well delineated (Alessi 1998, Brazil 2004, Brunet 1999, Chan 1999, Coffer 1998, Datta 1999, Downward 1998, Franke 1997, Hanada 2004, Hemmings 1997, Kops 2002, Scheid 2003, Simpson 2001, Testa 2001, Vivanco 2002), and new substrates continue to be validated in vivo. It is currently less clear, however, whether AKT1, AKT2, and AKT3 are functionally redundant or whether each carries out a specific functional role (Bellacosa et al., 2004). In this review, we summarize current knowledge regarding the signaling properties and specificities of the various AKT kinases emerging from recent studies of human cancers and rodent models, as well as the status of current efforts to specifically target individual AKT family members and other upstream and downstreamcomponents of this pathway to maximize therapeutic efficacy. While AKT kinases are promising targets for pharmacological intervention, increased understanding of the distinct roles of each AKT family member could lead to improved design of highly specific targeted therapies having reduced toxicities and improved efficacy.