Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises

doi:10.1016/j.coph.2008.08.004

Current Opinion in Pharmacology

Volume 8, Issue 4, August 2008, Pages 393-412

https://doi.org/10.1016/j.coph.2008.08.004 Get rights and content

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.

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.

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Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises

Section snippets

PI3K deregulation in cancer

Combination strategies through horizontal or vertical blockade of the pathway

The need for biomarkers to accelerate anticancer drug development

Pitfalls and promises in targeting this pathway

Conclusion

Disclosures

References and recommended reading

Acknowledgements

Adv Cancer Res

Cell

Trends Biochem Sci

Trends Biochem Sci

Cancer Cell

Cell

Drug Resist Updat

Cell Cycle

Biochem J

Cytogenet Cell Genet

Cancer Res

Mol Cancer Ther

Cancer Biol Ther

Invest New Drugs

Breast Cancer Res Treat

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