Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises
Section snippets
PI3K deregulation in cancer
The PI3K family of lipid kinases consists of at least eight proteins with shared sequence homology within their kinase domains, but with different substrate specificities and modes of regulation. The best known members are the four Class I PI3K isoforms (α, β, δ, and γ), which convert PIP2 to PIP3, and are associated with carcinogenesis [13]. Although only the p110α isoform is mutated in human cancers, the other forms also have oncogenic potential when overexpressed [29]. The role of these
Combination strategies through horizontal or vertical blockade of the pathway
The primary biological effect of the PI3K inhibitors is cytostatic, causing a G1 arrest following down-regulation of cyclin D1 [49••]. Hence they are only likely to induce disease stabilization as single agents. In view of this, combination strategies with either cytotoxic chemotherapies or other targeted agents will be necessary for the optimal use of these inhibitors. Such strategies may involve either vertical or horizontal blockade. The concept of vertical blockade, involving one or more
The need for biomarkers to accelerate anticancer drug development
The development of novel anticancer drugs remains a slow, costly, and inefficient process, with only a small proportion of agents reaching regulatory approval [16]. One of the crucial elements to improving the success rate of PI3K, AKT, and mTOR inhibitors is through the use of analytically validated and clinically qualified biomarkers developed in tandem with these novel agents [138, 16].
Pitfalls and promises in targeting this pathway
It is only with robust commitment and collaboration between academic oncologists, industry and the regulatory authorities to ongoing translational research that significant improvements in patient outcomes can be attained beyond the marginal gains attained in many instances thus far. Great progress has been made in understanding tumor biology and a substantial number of novel therapies that may potentially transform the outcome of cancer treatment are now available to patients, albeit mainly in
Conclusion
There is an impressive and increasing armamentarium of targeted agents that inhibit the key components of the PI3K–AKT–mTOR pathway and many of these are already in clinical trials. It is thus imperative that effective agents with the potential to maximize patient benefit and minimize toxicities are carefully selected and brought promptly to regulatory approval. It will be important to utilize biomarkers to select appropriate patients and to provide proof of target modulation to aid in the
Disclosures
Timothy Yap, Michelle Garrett, Mike Walton, Florence Raynaud, Johann de Bono and Paul Workman are employees of The Institute of Cancer Research which has a commercial interest in the development of PI3 kinase and AKT inhibitors. The Institute has been involved in a funded research collaboration to develop PI3 kinase inhibitors with Astellas Pharma and Piramed Pharma (recently acquired by Roche) and intellectual property has been licensed to Genentech. The Institute has also been involved in a
References and recommended reading
Papers of particular interest have been highlighted as:
● of special interest
●● of outstanding interest
Acknowledgements
Work in the authors’ laboratory is funded by Cancer Research UK [CUK] programme grant number C309/A8274. Johann de Bono is funded by Cancer Research UK [CUK] programme grant number C1178/A7851. Paul Workman is a Cancer Research UK Life Fellow and Timothy Yap is a Cancer Research UK Clinical Research Fellow. The authors would like to thank Dr John Caldwell for the assistance with chemical structures.
References (185)
- et al.
Activation of AKT kinases in cancer: implications for therapeutic targeting
Adv Cancer Res
(2005) - et al.
AKT/PKB signaling: navigating downstream
Cell
(2007) - et al.
The PI3K inhibitor arsenal: choose your weapon!
Trends Biochem Sci
(2007) - et al.
Cancer-specific mutations in phosphatidylinositol 3-kinase
Trends Biochem Sci
(2007) - et al.
PTEN and p53: who will get the upper hand?
Cancer Cell
(2003) - et al.
Tenets of PTEN tumor suppression
Cell
(2008) - et al.
Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations
Drug Resist Updat
(2008) - et al.
PI 3-kinases: hidden potentials revealed
Cell Cycle
(2006) - et al.
Pharmacokinetics and metabolism of the phospatidylinositol 3-kinase inhibitor LY294002 in the mouse [abstract #2044]
- et al.
The selectivity of protein kinase inhibitors: a further update
Biochem J
(2007)
XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR [Abstract B250]
Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization
Cytogenet Cell Genet
Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt
Cancer Res
Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways
Mol Cancer Ther
A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer
Cancer Biol Ther
A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial
Invest New Drugs
A Phase 2 study of perifosine in advanced or metastatic breast cancer
Breast Cancer Res Treat
A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study
Am J Clin Oncol
The phosphatidylinositol 3-kinase AKT pathway in human cancer
Nat Rev Cancer
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Nat Rev Genet
Exploiting the PI3K/AKT pathway for cancer drug discovery
Nat Rev Drug Discov
Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients
Int J Cancer
Ras, PI(3)K and mTOR signalling controls tumour cell growth
Nature
Phosphatidylinositol-3-OH kinase as a direct target of Ras
Nature
Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas
Cancer Res
Mutation of the PIK3CA gene in ovarian and breast cancer
Cancer Res
High frequency of mutations of the PIK3CA gene in human cancers
Science
PIK3CA is implicated as an oncogene in ovarian cancer
Nat Genet
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
Proc Natl Acad Sci U S A
Pharmacodynamic biomarkers for molecular cancer therapeutics
Adv Cancer Res
PI3K/Akt signalling pathway and cancer
Cancer Treat Rev
Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas
Oncology
Cancer. Addiction to oncogenes — the Achilles heal of cancer
Science
Mechanisms of disease: oncogene addiction — a rationale for molecular targeting in cancer therapy
Nat Clin Pract Oncol
Deregulation of the Akt pathway in human cancer
Curr Cancer Drug Targets
Drugging the PI3 kinome
Nat Biotechnol
The Akt/PKB pathway: molecular target for cancer drug discovery
Oncogene
Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation
Nature
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling
Cell
A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002)
J Biol Chem
A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity
Cancer Res
Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of SF1126 a vascular targeted pan phosphoinositide 3-kinase (PI3K) inhibitor in patients with solid tumors
J Clin Oncol
PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors
Cancer Biol Ther
Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models
J Med Chem
The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts
Mol Cancer Ther
The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures
Mol Cancer Ther
Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling
Mol Cancer Ther
Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement
J Immunol
Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury
Proc Natl Acad Sci U S A
Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor
J Natl Cancer Inst
Cited by (488)
Diisobutyl phthalate (DiBP)-induced male germ cell toxicity and its alleviation approach
2024, Food and Chemical ToxicologyPyridaben impaired cell cycle progression through perturbation of calcium homeostasis and PI3K/Akt pathway in zebrafish hepatocytes
2024, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyPiperlongumine induces apoptosis and autophagy via the PI3K/Akt/mTOR pathway in KB human cervical cancer cells
2023, Food and Chemical ToxicologyMetabolomics of the interaction between a consortium of entomopathogenic fungi and their target insect: Mechanisms of attack and survival
2023, Pesticide Biochemistry and Physiology