PI3K pathway alterations in cancer: variations on a theme
Open accessAbstract
The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110 alpha catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.
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The PI3K pathway is hyperactivated not only in GBM, but also in many other cancers including breast, ovarian, endometrial, lung, prostate, renal and lymphocyte.
“Furthermore, the PI3K pathway is hyperactivated not only in GBM, but also in many other cancers including breast, ovarian, endometrial, lung, prostate, renal and lymphocyte (5, 56–58).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [57]
The Introduction and Known mutations in the pathway sections describe widespread PI3K-pathway dysregulation in cancer. The glioblastoma, HER2, and PTEN sections provide examples involving GBM and breast, ovarian, endometrial, lung, and prostate cancers. Our copy does not establish the claim for renal cancer or lymphocyte-derived cancer; its Immune cells section discusses PI3K activation in immune cells within the tumor environment, not cancers of those cells. No page numbers were available in the indexed passages. (LLM, conf=0.88)
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The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
Self-citation<i>MET</i> Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496 · see citing works
Self-citationNagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858 · see citing works
Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.030 · Cited by 1,627 · see citing works
Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
Samuels, Y., Diaz, L. A., Schmidt-Kittler, O., Cummins, J. M., DeLong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.014 · Cited by 915 · see citing works
Intragenic ERBB2 kinase mutations in tumours
Stephens, P., Hunter, C., Bignell, G., Edkins, S., Davies, H., Teague, J., Stevens, C., O'Meara, S., Smith, R., Parker, A., et al. (2004) · Nature · doi:10.1038/431525b · Cited by 802 · see citing works
The PIK3CA gene is mutated with high frequency in human breast cancers
Bachman, K. E., Argani, P., Samuels, Y., Silliman, N., Ptak, J., Szabo, S., Konishi, H., Karakas, B., Blair, B. G., Lin, C., et al. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.8.994 · Cited by 665 · see citing works
Jhawer, M., Goel, S., Wilson, A. J., Montagna, C., Ling, Y.-H., Byun, D.-S., Nasser, S., Arango, D., Shin, J., Klampfer, L., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5659 · Cited by 460 · see citing works
Flagged first, then by citations
Research works printed but not linked: 77
- Abubaker J Bavi P Al-Harbi S Ibrahim M Siraj AK Al-Sanea N Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population Oncogene 2008 27 3539 3545 18193083
- Arteaga CL EGF receptor mutations in lung cancer: from humans to mice and maybe back to humans Cancer Cell 2006 9 421 423 16766261
- Barault L Veyrie N Jooste V Lecorre D Chapusot C Ferraz JM Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers Int J Cancer 2008 122 2255 2259 18224685
- Barnes KR Blois J Smith A Yuan H Reynolds F Weissleder R Fate of a bioactive fluorescent wortmannin derivative in cells Bioconjug Chem 2008 19 130 137 17988080
- Bauer S Duensing A Demetri GD Fletcher JA KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway Oncogene 2007 26 7560 7568 17546049
- Bissell MJ Radisky D Putting tumours in context Nat Rev Cancer 2001 1 46 54 11900251 PMC2975572
- Buck E Eyzaguirre A Brown E Petti F McCormack S Haley JD Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors Mol Cancer Ther 2006 5 2676 2684 17121914
- Carpten JD Faber AL Horn C Donoho GP Briggs SL Robbins CM A transforming mutation in the pleckstrin homology domain of AKT1 in cancer Nature 2007 448 439 444 17611497
- Chen JS Zhou LJ Entin-Meer M Yang X Donker M Knight ZA Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma Mol Cancer Ther 2008 7 841 850 18413797
- Chen Z Trotman LC Shaffer D Lin HK Dotan ZA Niki M Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis Nature 2005 436 725 730 16079851 PMC1939938
- Crabbe T Welham MJ Ward SG The PI3K inhibitor arsenal: choose your weapon! Trends Biochem Sci 2007 32 450 456 17920279
- Downward J Targeting RAS signalling pathways in cancer therapy Nat Rev Cancer 2003 3 11 22 12509763
- Engelman JA The role of phosphoinositide 3-kinase pathway inhibitors in the treatment of lung cancer Clin Cancer Res 2007 13 s4637 s4640 17671156
- Engelman JA Janne PA Mermel C Pearlberg J Mukohara T Fleet C ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines Proc Natl Acad Sci USA 2005 102 3788 3793 15731348 PMC553328
- Engelman JA Luo J Cantley LC The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism Nat Rev Genet 2006 7 606 619 16847462
- Fan QW Cheng CK Nicolaides TP Hackett CS Knight ZA Shokat KM A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma Cancer Res 2007 67 7960 7965 17804702 PMC2597547
- Fan QW Knight ZA Goldenberg DD Yu W Mostov KE Stokoe D A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma Cancer Cell 2006 9 341 349 16697955 PMC2925230
- Folkman J Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007 6 273 286 17396134
- Fujita T Doihara H Kawasaki K Takabatake D Takahashi H Washio K PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer Br J Cancer 2006 94 247 252 16404430 PMC2361109
- Furuyama T Kitayama K Shimoda Y Ogawa M Sone K Yoshida-Araki K Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice J Biol Chem 2004 279 34741 34749 15184386
- Garlich JR De P Dey N Su JD Peng X Miller A A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity Cancer Res 2008 68 206 215 18172313
- Graupera M Guillermet-Guibert J Foukas LC Phng LK Cain RJ Salpekar A Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration Nature 2008 453 662 666 18449193
- Gupta GP Massague J Cancer metastasis: building a framework Cell 2006 127 679 695 17110329
- Gupta S Ramjaun AR Haiko P Wang Y Warne PH Nicke B Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice Cell 2007 129 957 968 17540175
- Hamada K Sasaki T Koni PA Natsui M Kishimoto H Sasaki J The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis Genes Dev 2005 19 2054 2065 16107612 PMC1199575
- Harrington LS Findlay GM Gray A Tolkacheva T Wigfield S Rebholz H The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins J Cell Biol 2004 166 213 223 15249583 PMC2172316
- Heinrich MC Corless CL Duensing A McGreevey L Chen CJ Joseph N PDGFRA activating mutations in gastrointestinal stromal tumors Science 2003 299 708 710 12522257
- Hendriks BS Opresko LK Wiley HS Lauffenburger D Coregulation of epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) levels and locations: quantitative analysis of HER2 overexpression effects Cancer Res 2003 63 1130 1137 12615732
- Hirata A Hosoi F Miyagawa M Ueda S Naito S Fujii T HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells Cancer Res 2005 65 4253 4260 15899817
- Hirsch E Ciraolo E Ghigo A Costa C Taming the PI3K team to hold inflammation and cancer at bay Pharmacol Ther 2008 118 192 205 18420279
- Hirsch E Katanaev VL Garlanda C Azzolino O Pirola L Silengo L Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation Science 2000 287 1049 1053 10669418
- Hofer E Schweighofer B Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis Thromb Haemost 2007 97 355 363 17334501 PMC2879321
- Hollestelle A Elstrodt F Nagel JH Kallemeijn WW Schutte M Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines Mol Cancer Res 2007 5 195 201 17314276
- Howes AL Chiang GG Lang ES Ho CB Powis G Vuori K The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures Mol Cancer Ther 2007 6 2505 2514 17766839
- Huang CH Mandelker D Schmidt-Kittler O Samuels Y Velculescu VE Kinzler KW The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations Science 2007 318 1744 1748 18079394
- Ikeda T Yoshinaga K Suzuki A Sakurada A Ohmori H Horii A Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer Oncol Rep 2000 7 567 570 10767369
- Isakoff SJ Engelman JA Irie HY Luo J Brachmann SM Pearline RV Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells Cancer Res 2005 65 10992 11000 16322248
- Kang S Seo SS Chang HJ Yoo CW Park SY Dong SM Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma Int J Gynecol Cancer 2008 e-pub ahead of print. 18221484
- Kato S Iida S Higuchi T Ishikawa T Takagi Y Yasuno M PIK3CA mutation is predictive of poor survival in patients with colorectal cancer Int J Cancer 2007 121 1771 1778 17590872
- Kim JS Lee C Bonifant CL Ressom H Waldman T Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA Mol Cell Biol 2007 27 662 677 17060456 PMC1800819
- Knight ZA Gonzalez B Feldman ME Zunder ER Goldenberg DD Williams O A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling Cell 2006 125 733 747 16647110 PMC2946820
- Kolsch V Charest PG Firtel RA The regulation of cell motility and chemotaxis by phospholipid signaling J Cell Sci 2008 121 551 559 18287584 PMC2671295
- Kong D Yamori T ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms Cancer Sci 2007 98 1638 1642 17711503 PMC11158993
- Koyasu S The role of PI3K in immune cells Nat Immunol 2003 4 313 319 12660731
- Li D Shimamura T Ji H Chen L Haringsma HJ McNamara K Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy Cancer Cell 2007 12 81 93 17613438
- Lim KH Counter CM Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance Cancer Cell 2005 8 381 392 16286246
- Martin-Belmonte F Mostov K Regulation of cell polarity during epithelial morphogenesis Curr Opin Cell Biol 2008 20 227 234 18282696
- Mellinghoff IK Wang MY Vivanco I Haas-Kogan DA Zhu S Dia EQ Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N Engl J Med 2005 353 2012 2024 16282176
- Miled N Yan Y Hon WC Perisic O Zvelebil M Inbar Y Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit Science 2007 317 239 242 17626883
- Moasser MM The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis Oncogene 2007 26 6469 6487 17471238 PMC3021475
- Narita Y Nagane M Mishima K Huang HJ Furnari FB Cavenee WK Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas Cancer Res 2002 62 6764 6769 12438278
- Oda K Stokoe D Taketani Y McCormick F High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma Cancer Res 2005 65 10669 10673 16322209
- Ollikainen M Gylling A Puputti M Nupponen NN Abdel-Rahman WM Butzow R Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma Int J Cancer 2007 121 915 920 17471559
- Perez-Tenorio G Alkhori L Olsson B Waltersson MA Nordenskjold B Rutqvist LE PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer Clin Cancer Res 2007 13 3577 3584 17575221
- Ramjaun AR Downward J Ras and phosphoinositide 3-kinase: partners in development and tumorigenesis Cell Cycle 2007 6 2902 2905 17993782
- Rodriguez-Viciana P Warne PH Dhand R Vanhaesebroeck B Gout I Fry MJ Phosphatidylinositol-3-OH kinase as a direct target of Ras Nature 1994 370 527 532 8052307
- Rommel C Camps M Ji H PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007 7 191 201 17290298
- Saal LH Holm K Maurer M Memeo L Su T Wang X PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma Cancer Res 2005 65 2554 2559 15805248
- Salmena L Carracedo A Pandolfi PP Tenets of PTEN tumor suppression Cell 2008 133 403 414 18455982
- Samuels Y Wang Z Bardelli A Silliman N Ptak J Szabo S High frequency of mutations of the PIK3CA gene in human cancers Science 2004 304 554 15016963
- Sarkisian CJ Keister BA Stairs DB Boxer RB Moody SE Chodosh LA Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis Nat Cell Biol 2007 9 493 505 17450133
- Sauter G Maeda T Waldman FM Davis RL Feuerstein BG Patterns of epidermal growth factor receptor amplification in malignant gliomas Am J Pathol 1996 148 1047 1053 8644846 PMC1861518
- Soltoff SP Carraway KL III Prigent SA Gullick WG Cantley LC ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor Mol Cell Biol 1994 14 3550 3558 7515147 PMC358722
- Stommel JM Kimmelman AC Ying H Nabioullin R Ponugoti AH Wiedemeyer R Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies Science 2007 318 287 290 17872411
- Suire S Hawkins P Stephens L Activation of phosphoinositide 3-kinase gamma by Ras Curr Biol 2002 12 1068 1075 12121613
- Sun JF Phung T Shiojima I Felske T Upalakalin JN Feng D Microvascular patterning is controlled by fine-tuning the Akt signal Proc Natl Acad Sci USA 2005 102 128 133 15611473 PMC538747
- Tokunaga E Oki E Kimura Y Yamanaka T Egashira A Nishida K Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma Breast Cancer Res Treat 2007 101 249 257 17006756
- Tornillo L Terracciano LM An update on molecular genetics of gastrointestinal stromal tumours J Clin Pathol 2006 59 557 563 16731599 PMC1860404
- Velho S Oliveira C Ferreira A Ferreira AC Suriano G Schwartz S Jr The prevalence of PIK3CA mutations in gastric and colon cancer Eur J Cancer 2005 41 1649 1654 15994075
- Walker EH Pacold ME Perisic O Stephens L Hawkins PT Wymann MP Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine Mol Cell 2000 6 909 919 11090628
- Walker EH Perisic O Ried C Stephens L Williams RL Structural insights into phosphoinositide 3-kinase catalysis and signalling Nature 1999 402 313 320 10580505
- Wang MY Lu KV Zhu S Dia EQ Vivanco I Shackleford GM Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells Cancer Res 2006 66 7864 7869 16912159
- Wilhelm SM Carter C Tang L Wilkie D McNabola A Rong H BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis Cancer Res 2004 64 7099 7109 15466206
- Wymann MP Bulgarelli-Leva G Zvelebil MJ Pirola L Vanhaesebroeck B Waterfield MD Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction Mol Cell Biol 1996 16 1722 1733 8657148 PMC231159
- Yaguchi S Fukui Y Koshimizu I Yoshimi H Matsuno T Gouda H Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor J Natl Cancer Inst 2006 98 545 556 16622124
- Yuan H Barnes KR Weissleder R Cantley L Josephson L Covalent reactions of wortmannin under physiological conditions Chem Biol 2007 14 321 328 17379147
- Zhao L Vogt PK Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms Proc Natl Acad Sci USA 2008 105 2652 2657 18268322 PMC2268191
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Rozengurt, E., Sinnett-Smith, J., & Kisfalvi, K. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2229 · Cited by 247 · see citing works
Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T. W., & Wang, X. (2010) · Cell · doi:10.1016/j.cell.2010.10.010 · Cited by 222 · see citing works
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Zhang, L., Li, Y., Wang, Q., Chen, Z., Li, X., Wu, Z., Hu, C., Liao, D., Zhang, W., & Chen, Z.-S. (2020) · Molecular Cancer · doi:10.1186/s12943-019-1112-1 · Cited by 152 · see citing works
Klempner, S. J., Myers, A. P., & Cantley, L. C. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0063 · Cited by 148 · see citing works
Self-citationScheffler, M., Bos, M., Gardizi, M., König, K., Michels, S., Fassunke, J., Heydt, C., Künstlinger, H., Ihle, M., Ueckeroth, F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.2834 · Cited by 147 · see citing works
Brooks, R., Fuhler, G. M., Iyer, S., Smith, M. J., Park, M.-Y., Paraiso, K. H. T., Engelman, R. W., & Kerr, W. G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902844 · Cited by 140 · see citing works
Sai, J., Owens, P., Novitskiy, S. V., Hawkins, O. E., Vilgelm, A. E., Yang, J., Sobolik, T., Lavender, N., Johnson, A. C., McClain, C., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2142 · Cited by 138 · see citing works
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Temraz, S., Mukherji, D., & Shamseddine, A. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160922976 · Cited by 117 · see citing works
Chakrabarty, A., Rexer, B. N., Wang, S. E., Cook, R. S., Engelman, J. A., & Arteaga, C. L. (2010) · Oncogene · doi:10.1038/onc.2010.257 · Cited by 102 · see citing works
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Chan, K. T., Blake, S., Zhu, H., Kang, J., Trigos, A. S., Madhamshettiwar, P. B., Diesch, J., Paavolainen, L., Horvath, P., Hannan, R. D., et al. (2020) · Cell Death & Differentiation · doi:10.1038/s41418-019-0384-8 · Cited by 71 · see citing works
Knijnenburg, T. A., Klau, G. W., Iorio, F., Garnett, M. J., McDermott, U., Shmulevich, I., & Wessels, L. F. A. (2016) · Scientific Reports · doi:10.1038/srep36812 · Cited by 74 · see citing works
Chiron, D., Martin, P., Di Liberto, M., Huang, X., Ely, S., Lannutti, B. J., Leonard, J. P., Mason, C. E., & Chen-Kiang, S. (2013) · Cell Cycle · doi:10.4161/cc.24928 · Cited by 71 · see citing works
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Serebriiskii, I. G., Pavlov, V., Tricarico, R., Andrianov, G., Nicolas, E., Parker, M. I., Newberg, J., Frampton, G., Meyer, J. E., & Golemis, E. A. (2022) · Nature Communications · doi:10.1038/s41467-022-29227-2 · Cited by 55 · see citing works
Pitts, T. M., Newton, T. P., Bradshaw-Pierce, E. L., Addison, R., Arcaroli, J. J., Klauck, P. J., Bagby, S. M., Hyatt, S. L., Purkey, A., Tentler, J. J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113037 · Cited by 54 · see citing works
Auslander, N., Yizhak, K., Weinstock, A., Budhu, A., Tang, W., Wang, X. W., Ambs, S., & Ruppin, E. (2016) · Scientific Reports · doi:10.1038/srep29662 · Cited by 50 · see citing works
Fahey, J. M., Korytowski, W., & Girotti, A. W. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.04.013 · Cited by 38 · see citing works
Padala, R. R., Karnawat, R., Viswanathan, S. B., Thakkar, A. V., & Das, A. B. (2017) · Molecular BioSystems · doi:10.1039/c6mb00786d · Cited by 33 · see citing works
Recent advances of dual FGFR inhibitors as a novel therapy for cancer
Liang, Q., Wang, J., Zhao, L., Hou, J., Hu, Y., & Shi, J. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113205 · Cited by 32 · see citing works
Treatments on the Horizon: Breast Cancer Patients with Central Nervous System Metastases
Kaplan, A., Li, M. J., & Malani, R. (2022) · Current Oncology Reports · doi:10.1007/s11912-022-01206-2 · Cited by 4 · see citing works
- Authors
- Yuan, T. L., & Cantley, L. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Cantley, L C
- Venue
- Oncogene
- Published
- 2008-09-15
- Volume
- 27
- Issue
- 41
- Pages
- 5497-5510
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3398461
- OpenAlex
- W2146414563
- Cited by
- 1,845
- References
- 8
- Citations by year
- 2026: 26 · 2025: 56 · 2024: 62 · 2023: 77 · 2022: 70 · 2021: 94 · 2020: 89 · 2019: 110 · 2018: 107 · 2017: 115 · 2016: 139 · 2015: 136 · 2014: 161 · 2013: 124 · 2012: 135
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA127003)
- National Institute of General Medical Sciences (R01GM041890)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PI3K signaling, PI3K inhibitors, receptor tyrosine kinase, Akt, PTEN, oncogenic mechanisms, genetic alterations in cancer, targeted cancer therapy
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Enzyme Inhibitors, Humans, Models, Biological, Mutation, Neoplasms, Nuclear Proteins, Genes, ras, Transcription Factors, Signal Transduction, Genes, erbB-2, Phosphatidylinositol 3-Kinases, PTEN Phosphohydrolase
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