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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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“AKT is well established as the predominant PI3K effector in many cell types [5].”
BackgroundSelf-citationFang, W., Huang, Y., Gu, W., Gan, J., Wang, W., Zhang, S., Wang, K., Zhan, J., Yang, Y., Huang, Y., et al. (2020) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-141 · Cited by 97
“PI3KAKT-mTOR pathway activation plays an important role in EGFR-TKI resistant events (8-10).”
BackgroundMurthy, D., Attri, K. S., & Singh, P. K. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00335 · Cited by 96
“The initiation of the Akt signaling cascade stimulates NF-kB, hypoxiainducible factor-1α (HIF-1α), and Forkhead transcription factors (FoXO), in addition to regulation of the cell cycle and inhibition of apoptosis (Cardone et al., 1998; Ayabe, 1999; Brunet et al., 1999; Zhong et al., 2000).”
BackgroundActivating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer
Herberts, C., Murtha, A. J., Fu, S. Y. F., Wang, G., Schönlau, E., Xue, H., Lin, D., Gleave, A., Yip, S., Angeles, A., et al. (2020) · European Urology · doi:10.1016/j.eururo.2020.04.058 · Cited by 89
Liu, L.-X., Heng, J.-H., Deng, D.-X., Zhao, H., Zheng, Z.-Y., Liao, L., Lin, W., Xu, X., Li, E., & Xu, L. (2023) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2023.100551 · Cited by 91
Xia, Y., Zhu, J., Yang, R., Wang, H., Li, Y., & Fu, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1141601 · Cited by 87
“The PI3K/AKT/mTOR signalling pathway is one of the main pathways by which mammals regulate growth (91).”
BackgroundDrug repurposing for the treatment of glioblastoma multiforme
Abbruzzese, C., Matteoni, S., Signore, M., Cardone, L., Nath, K., Glickson, J. D., & Paggi, M. G. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0642-x · Cited by 87
Chen, F., Zhang, Y., Gibbons, D. L., Deneen, B., Kwiatkowski, D. J., Ittmann, M., & Creighton, C. J. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3378 · Cited by 87
“c4 411 (4) Differential expression profile associated with”
BackgroundSelf-citationZhang, Y., Yang, L., Kucherlapati, M. H., Chen, F., Hadjipanayis, A. G., Pantazi, A., Bristow, C. A., Lee, E. A., Mahadeshwar, H. S., Tang, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.025 · Cited by 84
Self-citationCracking the context-specific PI3K signaling code
Madsen, R. R., & Vanhaesebroeck, B. (2020) · Science Signaling · doi:10.1126/scisignal.aay2940 · Cited by 83
Yu, Y., Han, Y., Zhang, F., Gao, Z., Zhu, T., Dong, S., & Ma, M. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01736 · Cited by 81
Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress
Mehra, S., Deshpande, N., & Nagathihalli, N. (2021) · Cancers · doi:10.3390/cancers13174434 · Cited by 85
“Analyzing The Cancer Genome Atlas (TCGA) database of 32 cancer types revealed the involvement of PI3K and its downstream signaling components in mediating the pro-tumorigenic effect of K-Ras and other oncogenes in numerous human malignancies, including PDAC [11,12].”
MethodThe mixed blessing of AMPK signaling in Cancer treatments
Sadria, M., Seo, D., & Layton, A. T. (2022) · BMC Cancer · doi:10.1186/s12885-022-09211-1 · Cited by 86
PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications
Mohamed, E., Kumar, A., Zhang, Y., Wang, A. S., Chen, K. Y., Lim, Y., Shai, A., Taylor, J. W., Clarke, J. L., Hilz, S., et al. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac064 · Cited by 83
Self-citationPI3K/AKT signaling pathway as a critical regulator of Cisplatin response in tumor cells
Navaei, Z. N., Khalili‐Tanha, G., Zangouei, A. S., Abbaszadegan, M. R., & Moghbeli, M. (2021) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.32604/or.2022.025323 · Cited by 81
“AXL belongs to the receptor tyrosine kinase (RTK) protein family that activates PI3K/AKT pathway to promote cell proliferation and regulate tumor drug resistance [169,170].”
BackgroundmTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential
Lei, G., Zhuang, L., & Gan, B. (2021) · BioEssays · doi:10.1002/bies.202100093 · Cited by 82
“The PI3K-AKT-mTORC1 oncogenic signaling axis serves to coordinate extracellular growth factor stimulationwith cell proliferation, growth, and survival, and it is one of themost frequentlymutated pathways in human cancers.[66] Yi et al.”
BackgroundSun, Q., Li, S., Wang, Y., Peng, H., Zhang, X., Zheng, Y., Li, C., Li, L., Chen, R., Chen, X., et al. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-017-0034-y · Cited by 79
“Furthermore, mTOR activity is not only influenced by genomic alterations but also by epigenomic alterations of these signaling cascades [42].”
BackgroundSelf-citationThe emerging role of PI3K inhibitors for solid tumour treatment and beyond
Belli, C., Repetto, M., Anand, S. K., Porta, C., Subbiah, V., & Curigliano, G. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02221-1 · Cited by 78
“Various types of genomic alterations can dysregulate activity of all PI3K proteins, with PIK3CA/p110α being the most common gene altered detected in 14% of all solid tumours and rarely in haematological malignancies [2].”
BackgroundZhang, Y., Chen, F., Fonseca, N. A., He, Y., Fujita, M., Nakagawa, H., Zhang, Z., Brāzma, A., PCAWG Transcriptome Working Group, Amin, S. B., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13885-w · Cited by 75
Self-citationTargeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery
Li, T., Jiang, H., Tong, Y., & Lu, J. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0602-8 · Cited by 77
Medulloblastoma genomics in the modern molecular era
Kumar, R., Liu, A. P. Y., & Northcott, P. A. (2019) · Brain Pathology · doi:10.1111/bpa.12804 · Cited by 72
“While SMARCA4, PIK3CA and TP53 are commonly mutated across a variety of human cancers, mutations in CSNK2B highlight the essential role of WNT signaling in these tumors as it encodes the β-subunit of casein kinase II, a positive regulator of WNT signaling (21, 46, 61, 84, 115).”
BackgroundmTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis
Triki, M., Rinaldi, G., Planque, M., Broekaert, D., Winkelkotte, A. M., Maier, C. R., Raman, S. J., Vandekeere, A., Elsen, J. V., Orth, M. F., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107806 · Cited by 73
“This signature was defined as the sum of phosphoprotein levels of mTOR, 4E-BP1 (S65, T37/T46, and T70 RPPA features), P70S6K, and S6 (S235/S236 and S240/S244 features) andwas previously described in Zhang et al.(Zhang et al., 2017).”
MethodChen, Z., Tian, H., Yao, D.-M., Zhang, Y., Feng, Z., & Yang, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.738477 · Cited by 71
Self-citationCalsina, B., Castro‐Vega, L. J., Torres‐Pérez, R., Inglada‐Pérez, L., Currás-Freixes, M., Roldán‐Romero, J. M., Mančíková, V., Letón, R., Remacha, L., Santos, M., et al. (2019) · Theranostics · doi:10.7150/thno.35458 · Cited by 70
“[25], which were derived from the signature obtained in cell lines after treatment with PI3K/AKT/mTOR inhibitors [26], and performed a correlation analysis between miR-21-3p expression and the PI3K/AKT/mTOR drug sensitivity signature.”
BackgroundMethodInfluentialWang, R., Lu, X., & Yu, R. (2020) · Drug Design Development and Therapy · doi:10.2147/dddt.s251614 · Cited by 70
Jin, N., Keam, B., Cho, J., Lee, M. J., Kim, H. R., Torosyan, H., Jura, N., Ng, P. K. S., Mills, G. B., Li, H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci150335 · Cited by 68
“The remaining 37% of HNSCC-associated PIK3CA mutations are distributed throughout the p110α subunit and are collectively known as noncanonical mutations (4).”
BackgroundMethodSelf-citationLarge-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines
Zhao, W., Li, J., Chen, M.-J. M., Luo, Y., Ju, Z., Nesser, N. K., Johnson-Camacho, K., Boniface, C. T., Lawrence, Y., Pande, N. T., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.10.008 · Cited by 68
Self-citationThe role of mTOR in age-related diseases
Chrienová, Ž., Nepovimová, E., & Kuča, K. (2021) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2021.1955873 · Cited by 72
Zhang, C., Duan, Y., Xia, M., Dong, Y., Chen, Y., Zheng, L., Chai, S., Zhang, Q., Wei, Z., Liu, N., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0733 · Cited by 69
“The mTOR is a serine/ threonine kinase that forms two complexes mTORC1 and mTORC2 (4, 5).”
BackgroundPI3K/Akt/mTOR Signaling Pathway in Blood Malignancies—New Therapeutic Possibilities
Wiese, W., Barczuk, J., Racińska, O., Siwecka, N., Rozpędek‐Kamińska, W., Słupianek, A., Sierpiński, R., & Majsterek, I. (2023) · Cancers · doi:10.3390/cancers15215297 · Cited by 68
Chromophobe renal cell carcinoma: current and controversial issues
Moch, H., & Ohashi, R. (2020) · Pathology · doi:10.1016/j.pathol.2020.09.015 · Cited by 66
Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner
Madsen, R. R., Knox, R. G., Pearce, W. P., López, S., Mahler-Araujo, B. M., McGranahan, N., Vanhaesebroeck, B., & Semple, R. K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821093116 · Cited by 65
“are among the most frequently observed oncogenic events in a range of human tumors (4).”
BackgroundSui, X., Han, X., Chen, P., Wu, Q., Feng, J., Duan, T., Chen, X., Pan, T. S., Yan, L., Jin, T., et al. (2020) · Frontiers in Molecular Biosciences · doi:10.2139/ssrn.3667646 · Cited by 64
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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