Targeting the phosphoinositide 3-kinase pathway in cancer

KEY POINTS * The phosphoinositide 3-kinase (PI3K) pathway is a crucial signal transduction system linking the activation of receptor tyrosine kinases (RTKs), G protein-coupled receptors

(GPCRs) and oncogenes such as _RAS_ to multiple essential cellular functions. * The PI3K pathway is tightly controlled by a class of PI3Ks that generate the lipid second messenger

phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), and the tumor suppressor PTEN (phosphatase and tensin homologue), a lipid phosphatase that dephosphorylates PtdIns(3,4,5)P3,

thereby counteracting the actions of PI3Ks. * The PI3K pathway is one of the most frequently activated signalling pathways in human cancer. Oncogenic activation of this pathway commonly

occurs through activating mutations in the p110α isoform of PI3K or through loss of the PTEN tumour suppressor. * Inhibitors that target key components of this pathway, including PI3K, AKT

and mammalian target of rapamycin (mTOR), are being actively developed. Some of them have reached clinical trials in patients with various solid and haematological malignancies. Most PI3K

inhibitors developed to date are pan-PI3K inhibitors. * It may be desirable to generate isoform-specific PI3K inhibitors as PI3Ks have essential roles in a wide range of normal physiological

functions, including glucose homeostasis and immune responses. For example, by targeting p110α or p110β isoforms in solid tumours, potential drugs might avoid toxicity to the immune system,

which is largely dependent on p110δ and p110γ for function. * The presence of multiple nodes with feedback loops and crosstalk between pathways may affect therapeutic outcomes. Emerging

strategies, such as simultaneously targeting two kinases in the pathway or the combination of PI3K pathway inhibitors with drugs that target other pathways, may achieve optimal clinical

benefits. ABSTRACT The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions,

and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that

target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent

progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS PHOSPHOINOSITIDE KINASES IN CANCER: FROM MOLECULAR MECHANISMS TO THERAPEUTIC OPPORTUNITIES Article 03 April 2025 THE PRESENT AND FUTURE OF PI3K

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muscle growth, insulin response, and hyperlipidemia. _Cell Metab._ 3, 355–366 (2006). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank N. Gray and Q. Liu for

providing compound structures and helpful discussions. We thank the reviewers for their helpful suggestions. We apologize to colleagues whose primary papers were not cited owing to space

constraints. This work was supported in part by the National Institutes of Health (CA030002, CA089021 and CA050661 to T.M.R. and CA134502-01 to J.J.Z.), the Department of Defense for Cancer

Research (BC051565 to J.J.Z.), the V Foundation (J.J.Z.) and the Claudia Barr Program (J.J.Z.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Departments of Cancer Biology, Dana–Farber

Cancer Institute, Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA Pixu Liu, Hailing Cheng, Thomas M. Roberts & Jean J. Zhao Authors * Pixu Liu View author

publications You can also search for this author inPubMed Google Scholar * Hailing Cheng View author publications You can also search for this author inPubMed Google Scholar * Thomas M.

Roberts View author publications You can also search for this author inPubMed Google Scholar * Jean J. Zhao View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to Jean J. Zhao. ETHICS DECLARATIONS COMPETING INTERESTS T.M.R. and J.J.Z. hold consulting positions at Novartis. RELATED LINKS RELATED LINKS

DATABASES OMIM Bannayan–Riley–Ruvalcabas syndrome Cowden's syndrome FURTHER INFORMATION Jean J. Zhao's homepage GLOSSARY * Germline mutation A heritable change in the DNA that

occurred in a germ cell or the zygote at the single-cell stage. When transmitted to the next generation, a germline mutation is incorporated in every cell of the body. * Somatic mutation

Also referred to as an 'acquired mutation', this is an alteration in DNA that occurs in a somatic cell, in contrast to a mutation in a germ cell. * Allosteric inhibitor A molecule

that inhibits an enzyme by binding to a site other than the active site, causing a conformational change in the active site of the enzyme and thereby inhibiting its catalytic function. *

Thrombosis The formation or presence of a blood clot in a blood vessel. * Biomarker A characteristic that can be objectively measured and evaluated as an indicator of normal biological

processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. * Tumour angiogenesis The formation of new blood vessels that grow into the tumour, supplying

nutrients and oxygen to assist tumour growth. * Cancer chemoprevention The use of chemical compounds to intervene in the early precancerous stages of carcinogenesis, thereby preventing

tumour formation. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, P., Cheng, H., Roberts, T. _et al._ Targeting the phosphoinositide 3-kinase

pathway in cancer. _Nat Rev Drug Discov_ 8, 627–644 (2009). https://doi.org/10.1038/nrd2926 Download citation * Issue Date: August 2009 * DOI: https://doi.org/10.1038/nrd2926 SHARE THIS

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