Send Orders of Reprints at reprints@benthamscience.net Current Medicinal Chemistry, 2013, 20, ????-???? 1 0929-8673/13 $58.00+.00 © 2013 Bentham Science Publishers Targeting the Akt Kinase to Modulate Survival, Invasiveness and Drug Resistance of Cancer Cells Giuliana Cassinelli 1 , Valentina Zuco 1 , Laura Gatti 1 , Cinzia Lanzi 1 , Nadia Zaffaroni 1 , Diego Colombo 2 and Paola Perego 1,* 1 Fondazione IRCCS Istituto Nazionale Tumori via Amadeo 42, 20133 Milan, Italy; 2 Department of Medical Biotechnol- ogy and Translational Medicine, University of Milan, via Saldini, 50, 20133 Milan (Italy); Abstract: The deregulation of oncogenic signaling pathways which provide survival advantages to tumor cells is medi- ated by multiple cellular networks. Among them, the PI3K-Akt-mTOR axis, in particular the serine/threonine kinase Akt, is recognized as a key player. The kinase is hyperactivated due to a variety of mechanism including loss of PTEN, muta- tions in the PI3K catalytic subunit, receptor tyrosine kinase and Ras activation. Indeed, inappropriate activation of the Akt kinase is a common event in human tumors and Akt appears to be a critical player in cell survival that may also account for the therapeutic resistance and the invasive phenotype of tumors. Inhibition of Akt signalling results in apoptosis and growth inhibition of tumour cells with elevated Akt activity. A functional role in drug resistance is supported by evidence that tumor cells with acquired resistance to antitumor agents may display increased Akt activation and that treatment with molecularly targeted agents can activate feed-back loops involving Akt. This serine/threonine kinase may therefore repre- sent an amenable target for modulation of sensitivity to compounds with different molecular features due to its pleiotropic role in cell survival. Different types of Akt inhibitors [i.e., ATP mimetics and pleckstrin-homology (PH) domain binders] have been generated and some of them have reached the clinical setting. The present review focuses on the i) mechanisms implicating Akt in increased survival and invasive potential of tumor cells of different tumor types and ii) on the devel- opment of Akt inhibitors as modulators of drug resistance. Keywords: Akt, drug resistance, invasion, angiogenesis, Akt inhibitors. 1. INTRODUCTION Akt, the cellular homologue of the v-Akt murine thy- moma viral oncoprotein, has recently emerged as a key regu- lator of cell survival. Specifically, it participates in the com- plex cellular network that maintains cell survival in the con- text of the PI3K-Akt-mTOR axis, activated downstream of RTKs [1, 2]. Akt plays a role in the regulation of cell growth and proliferation as well as in cell metabolism. The kinase is implicated in the control of multiple physiological functions such as nervous system development, in which Akt regulates neuronal survival induced by growth factors, by counteract- ing apoptosis activation [3, 4]. In addition, Akt appears to be a hub at the center of several major cell signaling pathways deregulated in tumors as its activation has been demonstrated to regulate processes leading to tumor progression and me- tastases such as cell motility, control of morphological polar- ity during chemotaxis and angiogenesis [5, 6]. The available evidence supports that the Akt protein is implicated in feed- back loops that become activated when tumor cells are ex- posed to small molecules that target survival pathways [7]. Akt is a serine/threonine kinase also known as protein kinase B (PKB) due to the high homology to protein kinase *Address correspondence to this author at the Fondazione IRCSS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan, Italy; Tel: +39-02-23902237; Fax: +39-02-23902692; E-mail: paola.perego@istitutotumori.mi.it. A (PKA) and protein kinase C (PKC). In the human genome, genes coding for three highly homologous AKT isoforms have been identified, AKT1 (PKB), AKT2 (PKB) and AKT3 (PKB), all of which implicated in human cancer [8, 9]. Akt consists of a conserved domain structure with a N- terminal PH domain of around 110 amino acid residues, a central structurally conserved kinase domain of around 260 amino acid residues, and a carboxy-terminal regulatory do- main mainly consisting of hydrophobic amino acids (60 amino acid residues). In spite of the high structural homol- ogy, the physiological functions of the Akt isoforms are not super-imposable [8, 10, 11]. Studies carried out using knock- out mice show that some functions of Akt kinases are shared by the three isoforms, whereas others are isoform-specific. For instance, Akt2 has been shown to be relevant for glucose metabolism, Akt1 is more specifically involved in cell sur- vival pathways and growth control, whereas the role of Akt3, which is expressed predominantly in the brain is unclear [12, 13]. Determinants of Akt isoform-specific activity may be related to affinity for specific intracellular chaperones, sub- cellular localization, availability for interaction with phos- phatases, besides tissue- or cell-type-specific factors. Since the physiological functions of the different Akt kinases are not completely overlapping, Akt isoform-specific deregula- tion might differentially contribute to disease state and pro- gression [8]. During cancer biogenesis, Akt1 and Akt2 play differen- tial roles [11]. Surprising evidence emerges from studies