Available online at www.sciencedirect.com Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises Timothy A Yap 1,3 , Michelle D Garrett 1 , Mike I Walton 1 , Florence Raynaud 1 , Johann S de Bono 2,3 and Paul Workman 1 The strategy of ‘drugging the cancer kinome’ has led to the successful development and regulatory approval of several novel molecular targeted agents. The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway as a key potential target. This review details the role of the pathway in oncogenesis and the rationale for inhibiting its vital components. The focus will be on the progress made in the development of novel therapies for cancer treatment, with emphasis placed on agents that have entered clinical development. Strategies involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients and to provide proof of target modulation will also be highlighted. Finally, we discuss the issues and limitations involved with targeting the PI3K– AKT–mTOR pathway, and predict what the future may hold for these novel anticancer therapeutics. Addresses 1 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK 2 Section of Medicine, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK 3 The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK Corresponding author: Workman, Paul (paul.workman@icr.ac.uk) Current Opinion in Pharmacology 2008, 8:393–412 This review comes from a themed issue on Cancer Edited by Paul Workman and Johann de Bono Available online 27th August 2008 1471-4892/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2008.08.004 Background Introduction In recent years, the phosphatidylinositide 3-kinase (PI3K)–AKT signaling pathway has risen to prominence as a key regulator of cell cycle proliferation, growth, survival, protein synthesis, and glucose metabolism (Figure 1)[1]. The significance of this pathway in cancer stems from the abundant evidence that it is frequently deregulated by various genetic and epigenetic mechan- isms in a wide range of tumor types and there is now extensive evidence validating various components of this pathway as molecular targets in cancer (Table 1)[1,2]. Several comprehensive reviews have already described the key players of the PI3K–AKT pathway and their respective molecular functions and roles in human patho- genicity (Figure 1)[1–5]. This review will focus on the progress made in the development of novel therapies targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mammalian target of rapa- mycin (mTOR). Emphasis is on agents that have entered clinical development. We will also highlight the issues and limitations involved with targeting the PI3K–AKT pathway, and discuss what the future may hold for these novel anticancer strategies. Deregulation of pathway and role in oncogenesis AKT is a central node in a complex cascade of signaling pathways, with cross-talk and feedback loops that influ- ence the regulation of this kinase (Figure 1). Aberrant AKT hyperactivation often occurs in cancer through a number of mechanisms. These include mutations or amplifications affecting upstream regulators, such as over- expression of ErbB2 in breast carcinoma (Table 1)[2,6]. Mutations of the Ras family are also frequent and are known to activate PI3K, for example in colorectal and pancreatic cancers [7,8]. Genetic amplification or mutation of PIK3CA, which encodes the p110a catalytic subunit of PI3K, has been observed in ovarian, colorectal, breast, gastric, brain, and cervical tumors [9–12]. The PIK3CA mutations have been reported to occur at a cumulative frequency of 15% across all tumor types, suggesting that this may be the most commonly mutated kinase in the human genome [13]. The majority of PIK3CA mutations cluster in one of three small conserved hot spots within helical and kinase domains, while the rest are distributed over the PI3K coding sequence [11,14,15]. These genetic aberrations result in gain of enzymatic function, acti- vation of AKT signaling, and oncogenic transformation [2,14,16]. PI3K signaling is inhibited by PTEN through the depho- sphorylation of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), which is the lipid-signaling product of the Class I PI3Ks. The PTEN gene is commonly inactivated by mutation, deletion, or epigenetic silencing and is the second most commonly mutated tumor suppressor gene after p53 [4,17]. PTEN aberrations have been implicated in glioblastoma, endometrial, prostate, and other cancers (Table 1)[1,18]. www.sciencedirect.com Current Opinion in Pharmacology 2008, 8:393–412