Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises
Abstract
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.
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Efforts shifted to target signaling components downstream of Ras such as Raf-MEK-ERK and PI3K-AKT-mTOR.
“efforts shifted to target signaling components downstream of Ras such as Raf-MEK-ERK mitogen-activated protein kinases4 and the phosphoinositide 3-kinase-AKT-mTOR pathway5.”
From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [5]
Cites
PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., et al. (2006) · Nature · doi:10.1038/nature04747 · Cited by 817 · see citing works
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The mTOR Signalling Pathway in Human Cancer
Pópulo, H., Lopes, J. M., & Soares, P. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13021886 · Cited by 830 · see citing works
Discovery and characterization of small molecules that target the GTPase Ral
Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Meier, J., Hoffman, B., Owens, C., Wysoczynski, C. L., et al. (2014) · Nature · doi:10.1038/nature13713 · Cited by 150 · see citing works
- Authors
- Yap, T. A., Garrett, M. D., Walton, M. I., Raynaud, F., de Bono, J. S., & Workman, P.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Workman, Paul
- Venue
- Current Opinion in Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 8
- Issue
- 4
- Pages
- 393-412
- ISSN
- 1471-4892 (ISSN-L)
- OpenAlex
- W2087012714
- Cited by
- 543
- References
- 1
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 16 · 2023: 21 · 2022: 14 · 2021: 22 · 2020: 24 · 2019: 19 · 2018: 25 · 2017: 23 · 2016: 39 · 2015: 38 · 2014: 46 · 2013: 55 · 2012: 45
- FWCI
- 17.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK (C1178/A7851, C309/A8274)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- PI3K/AKT/mTOR pathway, PI3K inhibitors, AKT inhibitors, mTOR inhibitors, carcinogenesis, targeted cancer therapy, biomarkers, patient selection, drug resistance, anticancer agents
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Agents, Enzyme Inhibitors, Humans, Neoplasms, Protein Kinases, Signal Transduction, Biomarkers, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
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