The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
Open accessAbstract
Summary Molecular alterations involving PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.
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“In particular, the occurrence of E545K at exon 9 and H1047R at exon 20 is prevalent in cancers, and these mutations can constitutively activate PI3K signaling32,33.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [32]
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“In particular, the occurrence of E545K at exon 9 and H1047R at exon 20 is prevalent in cancers, and these mutations can constitutively activate PI3K signaling32,33.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [32]
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Citations
Cites
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BackgroundInfluentialmTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · cited 2×
“Furthermore, AKT phosphorylates TSC2 at multiple sites, to inhibit the GTPase-activating protein function of the TSC protein complex (consisting of TSC1, TSC2, and TBC1D7) toward Rheb, a RAS family member (Dibble and Manning, 2013; Laplante and Sabatini, 2012).”
BackgroundAKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · cited 1×
“AKT directly and indirectly phosphorylates many downstream proteins, including the GSKs, p27KIP1, FoxO transcription factors, MDM2, and BAD, to enhance cell survival and growth (Manning and Cantley, 2007).”
BackgroundMutational landscape and significance across 12 major cancer types
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., et al. (2013) · Nature · doi:10.1038/nature12634 · Cited by 4,419 · cited 3×
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BackgroundComprehensive molecular characterization of clear cell renal cell carcinoma
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Cited by
Sorted by citations
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.035 · Cited by 3,201
“Several pathways are featured in more detail as separate publications, including: (1) PI3K pathway (Zhang et al., 2017): aberrations in the PI3K pathway were found predominantly as activating events in PIK3CA (less commonly in PIK3CB) and inactivating events in PTEN or PIK3R1withPIK3CA and PTEN…”
BackgroundSelf-citationTargeting Ferroptosis as a Vulnerability in Cancer
Lei, G., Zhuang, L., & Gan, B. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00459-0 · Cited by 2,252
The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138
mTOR signalling and cellular metabolism are mutual determinants in cancer
Mossmann, D., Park, S., & Hall, M. N. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0074-8 · Cited by 1,088
Metadata
- Authors
- Zhang, Y., Kwok-Shing Ng, P., Kucherlapati, M., Chen, F., Liu, Y., Tsang, Y. H., de Velasco, G., Jeong, K. J., Akbani, R., Hadjipanayis, A., Pantazi, A., Bristow, C. A., Lee, E., Mahadeshwar, H. S., Tang, J., Zhang, J., Yang, L., Seth, S., Lee, S., Ren, X., Song, X., Sun, H., Seidman, J., Luquette, L. J., Xi, R., Chin, L., Protopopov, A., Westbrook, T. F., Shelley, C. S., Choueiri, T. K., Ittmann, M., Van Waes, C., Weinstein, J. N., Liang, H., Henske, E. P., Godwin, A. K., Park, P. J., Kucherlapati, R., Scott, K. L., Mills, G. B., Kwiatkowski, D. J., & Creighton, C. J.
- Affiliations
- Baylor College of Medicine (US)
- Brigham and Women's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Broad Institute (US)
- University of Wisconsin–Madison (US)
- Dana-Farber Cancer Institute (US)
- University of Kansas Medical Center (US)
- Corresponding author
- Mills, Gordon B.
- Kwiatkowski, David J.
- Creighton, Chad J.
- ORCID
- Zhang, Yiqun
- Kucherlapati, Melanie
- Chen, Fengju
- Liu, Yuexin
- Tsang, Yiu Huen
- Jeong, Kang Jin
- Akbani, Rehan
- Hadjipanayis, Angela
- Pantazi, Angeliki
- Bristow, Christopher A.
- Lee, Eunjung
- Zhang, Jianhua
- Yang, Lixing
- Seth, Sahil
- Lee, Semin
- Song, Xingzhi
- Seidman, Jonathan
- Luquette, Lovelace J.
- Xi, Ruibin
- Protopopov, Alexei
- Westbrook, Thomas F.
- Shelley, Carl Simon
- Choueiri, Toni K.
- Ittmann, Michael
- Weinstein, John N.
- Liang, Han
- Henske, Elizabeth P.
- Godwin, Andrew K.
- Park, Peter J.
- Mills, Gordon B.
- Kwiatkowski, David J.
- Creighton, Chad J.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 31
- Issue
- 6
- Pages
- 820-832.e3
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5502825
- OpenAlex
- W2616761213
- Semantic Scholar
- 1ca50d3272a9c1aa38b714579d66b2dff0588a2d
- Cited by
- 626
- References
- 45
- Citations by year
- 2026: 29 · 2025: 59 · 2024: 84 · 2023: 83 · 2022: 80 · 2021: 84 · 2020: 93 · 2019: 61 · 2018: 44 · 2017: 7
- FWCI
- 23.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP120713 C2, 5P50CA098258, 5U01CA168394)
- NIH (U24CA143883, 2P50CA101942-11A1, 1R21CA191687, 5P01CA120964, CA175486, CA209851, P30CA125123)
- Cancer Center (P30CA016672)
- Abbvie
- Adelson Medical Research Foundation
- AstraZeneca
- Breast Cancer Research Foundation
- Critical Outcomes Technology
- Horizon Diagnostics
- Illumina
- Ionis
- Karus Therapeutics
- Komen Research Foundation
- Nanostring
- Pfizer
- Takeda/Millennium Pharmaceuticals
- Tesaro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- PI3K/AKT/mTOR pathway, somatic mutations, copy number alterations, PTEN, STK11, structural variants, IDH1 mutation, VHL mutation, mutational hotspots
- MeSH terms
- Proteogenomics, Humans, Mutation, Neoplasms, Signal Transduction, Survival Analysis, Phosphatidylinositol 3-Kinases, Gene Expression Profiling, Databases, Genetic, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
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