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2000
Volume 31, Issue 31
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Breast cancer is a complex disease caused by the aberrant and unchecked proliferation of breast cells, which leads to the development of tumours. In various types of cancer, the Phosphoinositide 3-kinase/Protein kinase B (PKB, also known as Akt (PI3K/Akt) signalling pathway, is essential for controlling cell survival, metastasis, and metabolism. Currently, marketed PI3K inhibitors for treating breast cancer face several issues, including toxicity, resistance, . Significant efforts have been made to develop synthetic and repurposed inhibitor drugs to target PI3K, which are now being tested in clinical trials. Developed synthetic PI3K inhibitors have been reported to have better results in clinical trials in the suppression of tumors. This review article mainly focuses on the PI3K pathway at the cellular and molecular level, the development of PI3K inhibitors, and their clinical trials. Biomarkers, marine drugs, synthetic drugs, and repurposed drugs to treat breast cancer are also discussed, followed by mutational changes in PI3K and the resistance mechanism involved in PI3K inhibitors.

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2025-03-18
2025-10-22
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References

  1. CooperG.M. HausmanR.E. The development and causes of cancer.The Cell: A Molecular ApproachSunderland (MA)Sinauer Associates2000
    [Google Scholar]
  2. SuryaC. LakshminarayanaA.B.V. RameshS.H. KunjiappanS. TheivendrenP. Santhana Krishna KumarA. AmmunjeD.N. PavadaiP. Advancements in breast cancer therapy: The promise of copper nanoparticles.J. Trace Elem. Med. Biol.20248612752610.1016/j.jtemb.2024.12752639298835
    [Google Scholar]
  3. MakkerV. RecioF.O. MaL. MatulonisU.A. LauchleJ.O. ParmarH. GilbertH.N. WareJ.A. ZhuR. LuS. HuwL.Y. WangY. KoeppenH. SpoerkeJ.M. LacknerM.R. AghajanianC.A. A multicenter, single‐arm, open‐label, phase 2 study of apitolisib (GDC‐0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study).Cancer2016122223519352810.1002/cncr.3028627603005
    [Google Scholar]
  4. KalimuthuA.K. PanneerselvamT. PavadaiP. PandianS.R.K. SundarK. MurugesanS. AmmunjeD.N. KumarS. ArunachalamS. KunjiappanS. Pharmacoinformatics-based investigation of bioactive compounds of Rasam (South Indian recipe) against human cancer.Sci. Rep.20211112148810.1038/s41598‑021‑01008‑934728718
    [Google Scholar]
  5. HuK. LouL. TianW. PanT. YeJ. ZhangS. The outcome of breast cancer is associated with national human development index and health system attainment.PLoS One2016117e015895110.1371/journal.pone.015895127391077
    [Google Scholar]
  6. RadhakrishnaG.K. RameshS.H. AlmeidaS.D. SireeshaG. RameshS. TheivendrenP. KumarA.S.K. ChidamabaramK. AmmunjeD.N. KunjiappanS. PavadaiP. Capsaicin-entangled multi-walled carbon nanotubes against breast cancer: A theoretical and experimental approach.J. Cluster Sci.20243582849286910.1007/s10876‑024‑02694‑x
    [Google Scholar]
  7. FengY. SpeziaM. HuangS. YuanC. ZengZ. ZhangL. JiX. LiuW. HuangB. LuoW. LiuB. LeiY. DuS. VuppalapatiA. LuuH.H. HaydonR.C. HeT.C. RenG. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis.Genes Dis.2018527710610.1016/j.gendis.2018.05.00130258937
    [Google Scholar]
  8. BasileM.S. CavalliE. McCubreyJ. Hernández-BelloJ. Muñoz-ValleJ.F. FagoneP. NicolettiF. The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19.Drug Discov. Today202227384885610.1016/j.drudis.2021.11.00234763066
    [Google Scholar]
  9. DengS. DaiG. ChenS. NieZ. ZhouJ. FangH. PengH. Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3β signaling pathway.Biomed. Pharmacother.201911060260810.1016/j.biopha.2018.11.10330537677
    [Google Scholar]
  10. PaplomataE. O’ReganR. The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers.Ther. Adv. Med. Oncol.20146415416610.1177/175883401453002325057302
    [Google Scholar]
  11. XuJ. ZhengB. MaY. ZhangX. ChengJ. YangJ. LiP. ZhangJ. JingL. XuF. PI3K-AKT-mTOR signaling pathway regulates autophagy of hippocampal neurons in diabetic rats with chronic unpredictable mild stress.Behav. Brain Res.202345211455810.1016/j.bbr.2023.11455837390967
    [Google Scholar]
  12. KumarB.H. ManandharS. ChoudharyS.S. PriyaK. GujaranT.V. MehtaC.H. NayakU.Y. PaiK.S.R. Identification of phytochemical as a dual inhibitor of PI3K and mTOR: A structure-based computational approach.Mol. Divers.20232752015203610.1007/s11030‑022‑10541‑236244040
    [Google Scholar]
  13. RajalaR.V.S. Phosphoinositide 3-kinase signaling in the vertebrate retina.J. Lipid Res.201051142210.1194/jlr.R00023219638643
    [Google Scholar]
  14. LiuP. ChengH. RobertsT.M. ZhaoJ.J. Targeting the phosphoinositide 3-kinase pathway in cancer.Nat. Rev. Drug Discov.20098862764410.1038/nrd292619644473
    [Google Scholar]
  15. ButtiR. DasS. GunasekaranV.P. YadavA.S. KumarD. KunduG.C. Receptor tyrosine kinases (RTKs) in breast cancer: Signaling, therapeutic implications and challenges.Mol. Cancer20181713410.1186/s12943‑018‑0797‑x29455658
    [Google Scholar]
  16. JaberN. ZongW.X. Class III PI3K Vps34: Essential roles in autophagy, endocytosis, and heart and liver function.Ann. N. Y. Acad. Sci.201312801485110.1111/nyas.1202623551104
    [Google Scholar]
  17. ArcaroA. GuerreiroA. The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications.Curr. Genomics20078527130610.2174/13892020778244616019384426
    [Google Scholar]
  18. HopkinsB.D. GoncalvesM.D. CantleyL.C. Insulin-PI3K signalling: An evolutionarily insulated metabolic driver of cancer.Nat. Rev. Endocrinol.202016527628310.1038/s41574‑020‑0329‑932127696
    [Google Scholar]
  19. LienE.C. LyssiotisC.A. CantleyL.C. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. CramerT. SchmittC. Metabolism in CancerChamSpringer2016Vol 207397210.1007/978‑3‑319‑42118‑6_3
    [Google Scholar]
  20. HuangX. LiuG. GuoJ. SuZ. The PI3K/AKT pathway in obesity and type 2 diabetes.Int. J. Biol. Sci.201814111483149610.7150/ijbs.2717330263000
    [Google Scholar]
  21. NgY. RammG. LopezJ.A. JamesD.E. Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes.Cell Metab.20087434835610.1016/j.cmet.2008.02.00818396141
    [Google Scholar]
  22. HongS.Y. YuF.X. LuoY. HagenT. Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein.Cell. Signal.201628537738310.1016/j.cellsig.2016.01.01126826652
    [Google Scholar]
  23. SaxtonR.A. SabatiniD.M. mTOR signaling in growth, metabolism, and disease.Cell2017168696097610.1016/j.cell.2017.02.00428283069
    [Google Scholar]
  24. RobertsD.J. MiyamotoS. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy.Cell Death Differ.201522224825710.1038/cdd.2014.17325323588
    [Google Scholar]
  25. PorstmannT. SantosC.R. GriffithsB. CullyM. WuM. LeeversS. GriffithsJ.R. ChungY.L. SchulzeA. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.Cell Metab.20088322423610.1016/j.cmet.2008.07.00718762023
    [Google Scholar]
  26. MahajanK. MahajanN.P. PI3K‐independent AKT activation in cancers: A treasure trove for novel therapeutics.J. Cell. Physiol.201222793178318410.1002/jcp.2406522307544
    [Google Scholar]
  27. ProkopenkoI. PoonW. MägiR. Prasad BR. SalehiS.A. AlmgrenP. OsmarkP. Bouatia-NajiN. WierupN. FallT. StančákováA. BarkerA. LagouV. OsmondC. XieW. LahtiJ. JacksonA.U. ChengY.C. LiuJ. O’ConnellJ.R. BlomstedtP.A. FadistaJ. AlkayyaliS. DayehT. AhlqvistE. TaneeraJ. LecoeurC. KumarA. HanssonO. HanssonK. VoightB.F. KangH.M. Levy-MarchalC. VatinV. PalotieA. SyvänenA.C. MariA. WeedonM.N. LoosR.J.F. OngK.K. NilssonP. IsomaaB. TuomiT. WarehamN.J. StumvollM. WidenE. LakkaT.A. LangenbergC. TönjesA. RauramaaR. KuusistoJ. FraylingT.M. FroguelP. WalkerM. ErikssonJ.G. LingC. KovacsP. IngelssonE. McCarthyM.I. ShuldinerA.R. SilverK.D. LaaksoM. GroopL. LyssenkoV. A central role for GRB10 in regulation of islet function in man.PLoS Genet.2014104e100423510.1371/journal.pgen.100423524699409
    [Google Scholar]
  28. EngelmanJ.A. LuoJ. CantleyL.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.Nat. Rev. Genet.20067860661910.1038/nrg187916847462
    [Google Scholar]
  29. BriestF. GrabowskiP. PI3K-AKT-mTOR-signaling and beyond: The complex network in gastroenteropancreatic neuroendocrine neoplasms.Theranostics20144433636510.7150/thno.785124578720
    [Google Scholar]
  30. PetersenM.C. ShulmanG.I. Mechanisms of insulin action and insulin resistance.Physiol. Rev.20189842133222310.1152/physrev.00063.201730067154
    [Google Scholar]
  31. WilcoxG. Insulin and insulin resistance.Clin. Biochem. Rev.2005262193916278749
    [Google Scholar]
  32. ChudasamaK.K. WinnayJ. JohanssonS. ClaudiT. KönigR. HaldorsenI. JohanssonB. WooJ.R. AarskogD. SagenJ.V. KahnC.R. MolvenA. NjølstadP.R. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.Am. J. Hum. Genet.201393115015710.1016/j.ajhg.2013.05.02323810379
    [Google Scholar]
  33. HopkinsB.D. GoncalvesM.D. CantleyL.C. Obesity and cancer mechanisms: Cancer metabolism.J. Clin. Oncol.201634354277428310.1200/JCO.2016.67.971227903152
    [Google Scholar]
  34. MaffeiA. LemboG. CarnevaleD. PI3Kinases in diabetes mellitus and its related complications.Int. J. Mol. Sci.20181912409810.3390/ijms1912409830567315
    [Google Scholar]
  35. FrumanD.A. ChiuH. HopkinsB.D. BagrodiaS. CantleyL.C. AbrahamR.T. The PI3K pathway in human disease.Cell2017170460563510.1016/j.cell.2017.07.02928802037
    [Google Scholar]
  36. HeY. SunM.M. ZhangG.G. YangJ. ChenK.S. XuW.W. LiB. Targeting PI3K/Akt signal transduction for cancer therapy.Signal Transduct. Target. Ther.20216142510.1038/s41392‑021‑00828‑534916492
    [Google Scholar]
  37. WangM. ZhangJ. GongN. Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: A narrative review.Ann. Palliat. Med.202211280681710.21037/apm‑21‑328635016518
    [Google Scholar]
  38. GlavianoA. FooA.S.C. LamH.Y. YapK.C.H. JacotW. JonesR.H. EngH. NairM.G. MakvandiP. GeoergerB. KulkeM.H. BairdR.D. PrabhuJ.S. CarboneD. PecoraroC. TehD.B.L. SethiG. CavalieriV. LinK.H. Javidi-SharifiN.R. ToskaE. DavidsM.S. BrownJ.R. DianaP. StebbingJ. FrumanD.A. KumarA.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Mol. Cancer202322113810.1186/s12943‑023‑01827‑637596643
    [Google Scholar]
  39. FoxM. MottH.R. OwenD. Class IA PI3K regulatory subunits: p110-independent roles and structures.Biochem. Soc. Trans.20204841397141710.1042/BST2019084532677674
    [Google Scholar]
  40. HenryW.S. LaszewskiT. TsangT. BecaF. BeckA.H. McAllisterS.S. TokerA. Aspirin suppresses growth in PI3K-mutant breast cancer by activating AMPK and inhibiting mTORC1 signaling.Cancer Res.201777379080110.1158/0008‑5472.CAN‑16‑240027940576
    [Google Scholar]
  41. NavaeiZN Khalili-TanhaG. Sadra ZangoueiA. AbbaszadeganM. MoghbeliMR PI3K/AKT signaling pathway as a critical regulator of Cisplatin response in tumor cells.Oncol. Res.202129423525010.32604/or.2022.02532337303943
    [Google Scholar]
  42. FirooziniaM.F. JahromiM.Z.J. MoghadamtousiS.Z.M. NikzadS. KadirH.A.K. PIK3CA gene amplification and PI3K p110α protein expression in breast carcinoma.Int. J. Med. Sci.201411662062510.7150/ijms.825124782652
    [Google Scholar]
  43. MukoharaT. PI3K mutations in breast cancer: Prognostic and therapeutic implications.Breast Cancer (Dove Med. Press).20152311111710.2147/BCTT.S6069626028978
    [Google Scholar]
  44. LadewigE. MicheliniF. JhaveriK. CastelP. CarmonaJ. FairchildL. ZunigaA.G. Arruabarrena-AristorenaA. CoccoE. BlawskiR. KittaneS. ZhangY. SallakuM. BaldinoL. HristidisV. ChandarlapatyS. Abdel-WahabO. LeslieC. ScaltritiM. ToskaE. The oncogenic PI3K-induced transcriptomic landscape reveals key functions in splicing and gene expression regulation.Cancer Res.202282122269228010.1158/0008‑5472.CAN‑22‑044635442400
    [Google Scholar]
  45. StanciuS. Ionita-RaduF. StefaniC. MiricescuD. Stanescu-SpinuI.I. GreabuM. Ripszky TotanA. JingaM. Targeting PI3K/AKT/mTOR signaling pathway in pancreatic cancer: From molecular to clinical aspects.Int. J. Mol. Sci.202223171013210.3390/ijms23171013236077529
    [Google Scholar]
  46. LiuJ. GuX. GuanZ. HuangD. XingH. ZhengL. Role of m6A modification in regulating the PI3K/AKT signaling pathway in cancer.J. Transl. Med.202321177410.1186/s12967‑023‑04651‑037915034
    [Google Scholar]
  47. KompierL.C. LurkinI. van der AaM.N.M. van RhijnB.W.G. van der KwastT.H. ZwarthoffE.C. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.PLoS One2010511e1382110.1371/journal.pone.001382121072204
    [Google Scholar]
  48. HillmannP. FabbroD. PI3K/mTOR pathway inhibition: Opportunities in oncology and rare genetic diseases.Int. J. Mol. Sci.20192022579210.3390/ijms2022579231752127
    [Google Scholar]
  49. KlarenbeekS. van MiltenburgM.H. JonkersJ. Genetically engineered mouse models of PI3K signaling in breast cancer.Mol. Oncol.20137214616410.1016/j.molonc.2013.02.00323478237
    [Google Scholar]
  50. LinY. YangZ. XuA. DongP. HuangY. LiuH. LiF. WangH. XuQ. WangY. SunD. ZouY. ZouX. WangY. ZhangD. LiuH. WuX. ZhangM. FuY. CaiZ. LiuC. WuS. PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/CTNNB1 signaling pathway.Sci. Rep.201551899710.1038/srep0899725757764
    [Google Scholar]
  51. LiJ. JiangJ.L. ChenY.M. LuW.Q. KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway.J. Pathol. Clin. Res.20239542343510.1002/cjp2.32537147883
    [Google Scholar]
  52. EdrisA. AbdelrahmanM. OsmanW. SherifA.E. AshourA. GarelnabiE.A.E. IbrahimS.R.M. BafailR. SammanW.A. GhazawiK.F. MohamedG.A. AlzainA.A. Design of novel letrozole analogues targeting aromatase for breast cancer: Molecular docking, molecular dynamics, and theoretical studies on gold nanoparticles.Metabolites202313558310.3390/metabo1305058337233624
    [Google Scholar]
  53. TianL.Y. SmitD.J. JückerM. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism.Int. J. Mol. Sci.2023243265210.3390/ijms2403265236768977
    [Google Scholar]
  54. OnitiloA.A. EngelJ.M. GreenleeR.T. MukeshB.N. Breast cancer subtypes based on ER/PR and Her2 expression: Comparison of clinicopathologic features and survival.Clin. Med. Res.200971-241310.3121/cmr.2008.82519574486
    [Google Scholar]
  55. Orrantia-BorundaE. Anchondo-NuñezP. Acuña-AguilarL.E. Gómez-VallesF.O. Ramírez-ValdespinoC.A. Subtypes of breast cancer.Breast CancerBrisbane (AU)Exon Publications202210.36255/exon‑publications‑breast‑cancer‑subtypes36122153
    [Google Scholar]
  56. HigginsM.J. StearnsV. Understanding resistance to tamoxifen in hormone receptor-positive breast cancer.Clin. Chem.20095581453145510.1373/clinchem.2009.12537719541862
    [Google Scholar]
  57. LafcıO. CelepliP. Seher ÖztekinP. KoşarP.N. DCE-MRI radiomics analysis in differentiating luminal A and luminal B breast cancer molecular subtypes.Acad. Radiol.2023301222910.1016/j.acra.2022.04.00435595629
    [Google Scholar]
  58. GrassiniD. CascardiE. SarottoI. AnnaratoneL. SapinoA. BerrinoE. MarchiòC. Unusual patterns of HER2 expression in breast cancer: Insights and perspectives.Pathobiology202289527829610.1159/00052422735500561
    [Google Scholar]
  59. KumarP. AggarwalR. An overview of triple-negative breast cancer.Arch. Gynecol. Obstet.2016293224726910.1007/s00404‑015‑3859‑y26341644
    [Google Scholar]
  60. CollignonJ. LousbergL. SchroederH. JerusalemG. Triple-negative breast cancer: Treatment challenges and solutions.Breast Cancer (Dove Med. Press)201689310710.2147/BCTT.S6948827284266
    [Google Scholar]
  61. MutluM. SaatciÖ. AnsariS.A. YurdusevE. ShehwanaH. KonuÖ. RazaU. ŞahinÖ. miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer.Sci. Rep.2016613254110.1038/srep3254127600857
    [Google Scholar]
  62. EsnaashariS.S. MuhammadnejadS. AmanpourS. AmaniA. A combinational approach towards treatment of breast cancer: An analysis of noscapine-loaded polymeric nanoparticles and doxorubicin.AAPS PharmSciTech202021516610.1208/s12249‑020‑01710‑332504144
    [Google Scholar]
  63. Wise-DraperT.M. MoorthyG. SalkeniM.A. KarimN.A. ThomasH.E. MercerC.A. BegM.S. O’GaraS. OlowokureO. FathallahH. KozmaS.C. ThomasG. RixeO. DesaiP. MorrisJ.C. A phase Ib study of the dual PI3K/mTOR inhibitor dactolisib (BEZ235) combined with everolimus in patients with advanced solid malignancies.Target. Oncol.201712332333210.1007/s11523‑017‑0482‑928357727
    [Google Scholar]
  64. DollyS.O. WagnerA.J. BendellJ.C. KindlerH.L. KrugL.M. SeiwertT.Y. ZaudererM.G. LolkemaM.P. AptD. YehR.F. FredricksonJ.O. SpoerkeJ.M. KoeppenH. WareJ.A. LauchleJ.O. BurrisH.A. de BonoJ.S. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors.Clin. Cancer Res.201622122874288410.1158/1078‑0432.CCR‑15‑222526787751
    [Google Scholar]
  65. del CampoJ.M. BirrerM. DavisC. FujiwaraK. GollerkeriA. GoreM. HoukB. LauS. PovedaA. González-MartínA. MullerC. MuroK. PierceK. SuzukiM. VermetteJ. OzaA. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.Gynecol. Oncol.20161421626910.1016/j.ygyno.2016.04.01927103175
    [Google Scholar]
  66. SmythL.M. MonsonK.R. JhaveriK. DrilonA. LiB.T. AbidaW. IyerG. GerecitanoJ.F. GounderM. HardingJ.J. VossM.H. MakkerV. HoA.L. RazaviP. IasonosA. BialerP. LacoutureM.E. TeitcherJ.B. ErinjeriJ.P. KatabiN. FuryM.G. HymanD.M. A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.Invest. New Drugs201735674275010.1007/s10637‑017‑0445‑028281183
    [Google Scholar]
  67. RodonJ. BrañaI. SiuL.L. De JongeM.J. HomjiN. MillsD. Di TomasoE. SarrC. TrandafirL. MassacesiC. EskensF. BendellJ.C. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.Invest. New Drugs201432467068110.1007/s10637‑014‑0082‑924652201
    [Google Scholar]
  68. PatnaikA. ApplemanL.J. TolcherA.W. PapadopoulosK.P. BeeramM. RascoD.W. WeissG.J. SachdevJ.C. ChadhaM. FulkM. EjadiS. MountzJ.M. LotzeM.T. ToledoF.G.S. ChuE. JeffersM. PeñaC. XiaC. ReifS. GenvresseI. RamanathanR.K. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas.Ann. Oncol.201627101928194010.1093/annonc/mdw28227672108
    [Google Scholar]
  69. PatelV.M. BalakrishnanK. DouglasM. TibbittsT. XuE.Y. KutokJ.L. AyersM. SarkarA. GuerrieriR. WierdaW.G. O’BrienS. JainN. SternH.M. GandhiV. Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).Leukemia20173191872188110.1038/leu.2016.38228017967
    [Google Scholar]
  70. YamamotoN. FujiwaraY. TamuraK. KondoS. IwasaS. TanabeY. HoriikeA. YanagitaniN. KitazonoS. InataniM. TanakaJ. NishioM. Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer.Invest. New Drugs2017351374610.1007/s10637‑016‑0382‑327565810
    [Google Scholar]
  71. JuricD. KropI. RamanathanR.K. WilsonT.R. WareJ.A. Sanabria BohorquezS.M. SavageH.M. SampathD. SalphatiL. LinR.S. JinH. ParmarH. HsuJ.Y. Von HoffD.D. BaselgaJ. Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors.Cancer Discov.20177770471510.1158/2159‑8290.CD‑16‑108028331003
    [Google Scholar]
  72. JainS. ShahA.N. Santa-MariaC.A. SiziopikouK. RademakerA. HelenowskiI. CristofanilliM. GradisharW.J. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy.Breast Cancer Res. Treat.2018171237138110.1007/s10549‑018‑4792‑029850984
    [Google Scholar]
  73. KahlB.S. SpurgeonS.E. FurmanR.R. FlinnI.W. CoutreS.E. BrownJ.R. BensonD.M. ByrdJ.C. PetermanS. ChoY. YuA. GodfreyW.R. Wagner-JohnstonN.D. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL).Blood2014123223398340510.1182/blood‑2013‑11‑53755524615778
    [Google Scholar]
  74. SharmaS. GuruS.K. MandaS. KumarA. MintooM.J. PrasadV.D. SharmaP.R. MondheD.M. BharateS.B. BhushanS. A marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth and VEGF mediated angiogenesis by disrupting PI3K/Akt/mTOR signaling cascade.Chem. Biol. Interact.2017275476010.1016/j.cbi.2017.07.01728756150
    [Google Scholar]
  75. JinJ. ZhaoY. GuoW. WangB. WangY. LiuX. XuC. Thiocoraline mediates drug resistance in MCF-7 cells via PI3K/Akt/BCRP signaling pathway.Cytotechnology201971140140910.1007/s10616‑019‑00301‑w30689149
    [Google Scholar]
  76. DeyG. BhartiR. DasA.K. SenR. MandalM. Resensitization of Akt induced docetaxel resistance in breast cancer by ‘Iturin A’a lipopeptide molecule from marine bacteria Bacillus megaterium.Sci. Rep.2017711732410.1038/s41598‑017‑17652‑z29229973
    [Google Scholar]
  77. YuanJ. HeZ. WuJ. LinY. ZhuX. A novel adriamycin analogue derived from marine microbes induces apoptosis by blocking Akt activation in human breast cancer cells.Mol. Med. Rep.20114226126521468561
    [Google Scholar]
  78. ZhuX. HeZ. WuJ. YuanJ. WenW. HuY. JiangY. LinC. ZhangQ. LinM. ZhangH. YangW. ChenH. ZhongL. SheZ. ChenS. LinY. LiM. A marine anthraquinone SZ-685C overrides adriamycin-resistance in breast cancer cells through suppressing Akt signaling.Mar. Drugs201210469471110.3390/md1004069422690138
    [Google Scholar]
  79. El-BeltagiH.S. MohamedA.A. MohamedH.I. RamadanK.M.A. BarqawiA.A. MansourA.T. Phytochemical and potential properties of seaweeds and their recent applications: A review.Mar. Drugs202220634210.3390/md2006034235736145
    [Google Scholar]
  80. GhorbaniM. BigdeliB. Jalili-balehL. BaharifarH. AkramiM. DehghaniS. GoliaeiB. AmaniA. LotfabadiA. RashediH. HaririanI. AlamN.R. HamedaniM.P. KhoobiM. Curcumin-lipoic acid conjugate as a promising anticancer agent on the surface of gold‑iron oxide nanocomposites: A pH-sensitive targeted drug delivery system for brain cancer theranostics.Eur. J. Pharm. Sci.201811417518810.1016/j.ejps.2017.12.00829248558
    [Google Scholar]
  81. OsanlooM. YousefpoorY. AlipanahH. GhanbariasadA. JalilvandM. AmaniA. In-vitro assessment of essential oils as anticancer therapeutic agents: A systematic literature review.Jordan J. Pharm. Sci.202215217320310.35516/jjps.v15i2.319
    [Google Scholar]
  82. WuH.T. LiuY.E. HsuK.W. WangY.F. ChanY.C. ChenY. ChenD.R. MLL3 induced by luteolin causes apoptosis in tamoxifen-resistant breast cancer cells through H3K4 monomethylation and suppression of the PI3K/AKT/mTOR pathway.Am. J. Chin. Med.20204851221124110.1142/S0192415X2050060332668964
    [Google Scholar]
  83. LiX. ZhouN. WangJ. LiuZ. WangX. ZhangQ. LiuQ. GaoL. WangR. Quercetin suppresses breast cancer stem cells (CD44+/CD24− ) by inhibiting the PI3K/Akt/mTOR-signaling pathway.Life Sci.2018196566210.1016/j.lfs.2018.01.01429355544
    [Google Scholar]
  84. AfsarT. TrembleyJ.H. SalomonC.E. RazakS. KhanM.R. AhmedK. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways.Sci. Rep.2016612307710.1038/srep2307726975752
    [Google Scholar]
  85. SunY. ZhouQ.M. LuY.Y. ZhangH. ChenQ.L. ZhaoM. SuS.B. Resveratrol inhibits the migration and metastasis of MDA-MB-231 human breast cancer by reversing TGF-β1-induced epithelial-mesenchymal transition.Molecules2019246113110.3390/molecules2406113130901941
    [Google Scholar]
  86. LinC.H. ChangC.Y. LeeK.R. LinH.J. ChenT.H. WanL. Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway.BMC Cancer201515195810.1186/s12885‑015‑1965‑726675309
    [Google Scholar]
  87. RenJ. HuangQ. XuY. YangM. YangJ. HuK. Isoflavone lupiwighteone induces cytotoxic, apoptotic, and antiangiogenic activities in DU-145 prostate cancer cells.Anticancer Drugs201526659961110.1097/CAD.000000000000022425734831
    [Google Scholar]
  88. XueL. ZhangW.J. FanQ.X. WangL.X. Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells.Oncol. Lett.20181521869187329399197
    [Google Scholar]
  89. QinH.L. WangX.J. YangB.X. DuB. YunX.L. Notoginsenoside R1 attenuates breast cancer progression by targeting CCND2 and YBX3.Chin. Med. J. (Engl.)2021134554655410.1097/CM9.000000000000132833480613
    [Google Scholar]
  90. ParkJ.E. JiH.W. KimH.W. BaekM. JungS. KimS.J. Ginsenoside Rh2 regulates the cfap20dc-AS1/MicroRNA-3614-3p/BBX and TNFAIP3 Axis to induce apoptosis in breast cancer cells.Am. J. Chin. Med.20225061703171710.1142/S0192415X2250072035787669
    [Google Scholar]
  91. GouX. BaiH. LiuL. ChenH. ShiQ. ChangL. DingM. ShiQ. ZhouM. ChenW. ZhangL. Asiatic acid interferes with invasion and proliferation of breast cancer cells by inhibiting WAVE3 activation through PI3K/AKT signaling pathway.BioMed Res. Int.2020202011210.1155/2020/187438732104680
    [Google Scholar]
  92. PittellaF. DutraR.C. JuniorD.D. LopesM.T.P. BarbosaN.R. Antioxidant and cytotoxic activities of Centella asiatica (L) Urb.Int. J. Mol. Sci.20091093713372110.3390/ijms1009371319865514
    [Google Scholar]
  93. YangC. WangM. GongY. DengM. LingY. LiQ. WangJ. ZhouY. Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.Bioorg. Chem.202314010677910.1016/j.bioorg.2023.10677937579621
    [Google Scholar]
  94. ShettyC.R. ShastryC.S. ParasuramanP. HebbarS. Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.Bioimpacts20241442995110.34172/bi.2023.2995139104616
    [Google Scholar]
  95. DessaiP.G. DessaiS.P. DabholkarR. PednekarP. NaikS. MamledesaiS. GopalM. PavadaiP. KumarB.K. MurugesanS. ChandavarkarS. TheivendrenP. SelvarajK. Design, synthesis, graph theoretical analysis and molecular modelling studies of novel substituted quinoline analogues as promising anti-breast cancer agents.Mol. Divers.20232741567158610.1007/s11030‑022‑10512‑735976550
    [Google Scholar]
  96. DiaoW. ZhengJ. LiY. WangJ. XuS. Targeting histone demethylases as a potential cancer therapy (Review).Int. J. Oncol.202261310310.3892/ijo.2022.539335801593
    [Google Scholar]
  97. GutierrezD.A. ContrerasL. VillanuevaP.J. BorregoE.A. Morán-SantibañezK. HessJ.D. DeJesusR. LarragoityM. BetancourtA.P. MohlJ.E. Robles-EscajedaE. BegumK. RoyS. KirkenR.A. Varela-RamirezA. AguileraR.J. Identification of a potent cytotoxic pyrazole with anti-breast cancer activity that alters multiple pathways.Cells202211225410.3390/cells1102025435053370
    [Google Scholar]
  98. WangS. ZhangY. RenT. WuQ. LuH. QinX. LiuY. DingH. ZhaoQ. A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway.Cell Death Dis.202011649110.1038/s41419‑020‑2690‑y32606352
    [Google Scholar]
  99. XuL. JiangX. WeiF. ZhuH. Role of tropomyosin in silkworm allergy.Mol. Med. Rep.20181553264327010.3892/mmr.2017.637328339033
    [Google Scholar]
  100. LiangB. CuiS. ZouS. Leonurine suppresses prostate cancer growth in vitro and in vivo by regulating miR-18a-5p/SLC40A1 axis.Chin. J. Physiol.202265631932710.4103/0304‑4920.36545936588358
    [Google Scholar]
  101. ChenX. ZhaoM. HaoM. SunX. WangJ. MaoY. ZuL. LiuJ. ShenY. WangJ. ShenK. Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer.Mol. Cancer Res.201311101269127810.1158/1541‑7786.MCR‑13‑021223814023
    [Google Scholar]
  102. XieM. LiuJ. WangZ. SunB. WangJ. Inhibitory effects of 5-heptadecylresorcinol on the proliferation of human MCF-7 breast cancer cells through modulating PI3K/Akt/mTOR pathway.J. Funct. Foods20206910394610.1016/j.jff.2020.103946
    [Google Scholar]
  103. FathMK MasoulehRA AfifiN. LoghmaniS. TamimiP. FazeliA. MousavianS.A. FalsafiM.M. BaratiG. PI3K/AKT/mTOR signaling pathway modulation by circular RNAs in breast cancer progression.Pathol. Res. Pract.202324115427910.1016/j.prp.2022.15427936584499
    [Google Scholar]
  104. MariA. ManiG. NagabhishekS.N. BalaramanG. SubramanianN. MirzaF.B. SundaramJ. ThiruvengadamD. Carvacrol promotes cell cycle arrest and apoptosis through PI3K/AKT signaling pathway in MCF-7 breast cancer cells.Chin. J. Integr. Med.202127968068710.1007/s11655‑020‑3193‑532572774
    [Google Scholar]
  105. LiG. XuD. SunJ. ZhaoS. ZhengD. Paclitaxel inhibits proliferation and invasion and promotes apoptosis of breast cancer cells by blocking activation of the PI3K/AKT signaling pathway.Adv. Clin. Exp. Med.202029111337134510.17219/acem/12768133269821
    [Google Scholar]
  106. NoserA.A. ShehadiI.A. AbdelmonsefA.H. SalemM.M. Newly synthesized pyrazolinone chalcones as anticancer agents via inhibiting the PI3K/Akt/ERK1/2 signaling pathway.ACS Omega2022729252652527710.1021/acsomega.2c0218135910116
    [Google Scholar]
  107. MohamedM.F. MohamedM.S. ShoumanS.A. FathiM.M. AbdelhamidI.A. Synthesis and biological evaluation of a novel series of chalcones incorporated pyrazole moiety as anticancer and antimicrobial agents.Appl. Biochem. Biotechnol.201216851153116210.1007/s12010‑012‑9848‑822948604
    [Google Scholar]
  108. JasrilJ. New fluorinated chalcone and pyrazolines analogues: Synthesis, docking and molecular dynamic studies as anticancer agents.Thaiphesatchasan2017413939810.56808/3027‑7922.2402
    [Google Scholar]
  109. ShawishI. BarakatA. AldalbahiA. AlshaerW. DaoudF. AlqudahD.A. Al ZoubiM. HatmalM.M. NafieM.S. HaukkaM. SharmaA. de la TorreB.G. AlbericioF. El-FahamA. Acetic acid mediated for one-pot synthesis of novel pyrazolyl s-triazine derivatives for the targeted therapy of triple-negative breast tumor cells (MDA-MB-231) via EGFR/PI3K/AKT/mTOR signaling cascades.Pharmaceutics2022148155810.3390/pharmaceutics1408155836015186
    [Google Scholar]
  110. SarohaM. KhuranaJ.M. Acetic acid mediated regioselective synthesis of 2,4,5-trisubstituted thiazoles by a domino multicomponent reaction.New J. Chem.201943228644865010.1039/C9NJ01717H
    [Google Scholar]
  111. YanW. ZhaoY. HeJ. Anti‑breast cancer activity of selected 1,3,5‑triazines via modulation of EGFR‑TK.Mol. Med. Rep.20181854175418410.3892/mmr.2018.942630152850
    [Google Scholar]
  112. GruntT.W. MarianiG.L. Novel approaches for molecular targeted therapy of breast cancer: Interfering with PI3K/AKT/mTOR signaling.Curr. Cancer Drug Targets201313218820410.2174/156800961131302000823215720
    [Google Scholar]
  113. MaY. YangX. HanH. WenZ. YangM. ZhangY. FuJ. WangX. YinT. LuG. QiJ. LinH. WangX. YangY. Design, synthesis and biological evaluation of anilide (dicarboxylic acid) shikonin esters as antitumor agents through targeting PI3K/Akt/mTOR signaling pathway.Bioorg. Chem.202111110487210.1016/j.bioorg.2021.10487233838560
    [Google Scholar]
  114. BalochS.K. MaL. WangX.L. ShiJ. ZhuY. WuF.Y. PangY.J. LuG.H. QiJ.L. WangX.M. GuH-W. YangY-H. Design, synthesis and mechanism of novel shikonin derivatives as potent anticancer agents.RSC Advances2015540317593176710.1039/C5RA01872B
    [Google Scholar]
  115. YuY. HanY. ZhangF. GaoZ. ZhuT. DongS. MaM. Design, synthesis, and biological evaluation of imidazo [1, 2-a] pyridine derivatives as novel PI3K/mTOR dual inhibitors.J. Med. Chem.20206363028304610.1021/acs.jmedchem.9b0173632069401
    [Google Scholar]
  116. GaoH. LiZ. WangK. ZhangY. WangT. WangF. XuY. Design, synthesis, and biological evaluation of sulfonamide methoxypyridine derivatives as novel PI3K/mTOR dual inhibitors.Pharmaceuticals (Basel)202316346110.3390/ph1603046136986560
    [Google Scholar]
  117. DaoP. SmithN. Tomkiewicz-RauletC. Yen-PonE. Camacho-ArtachoM. LiethaD. HerbeuvalJ.P. CoumoulX. GarbayC. ChenH. Design, synthesis, and evaluation of novel imidazo[1,2-a][1,3,5]triazines and their derivatives as focal adhesion kinase inhibitors with antitumor activity.J. Med. Chem.201558123725110.1021/jm500784e25180654
    [Google Scholar]
  118. EsfandiariR. Moghimi-RadP. BuleM.H. SouriE. NadriH. MahdaviM. GhobadianR. AminiM. New imidazo[1,2-a]pyridin-2-yl derivatives as AChE, BChE, and LOX inhibitors; Design, synthesis, and biological evaluation.Lett. Drug Des. Discov.202320111784179810.2174/1570180819666220608111906
    [Google Scholar]
  119. CoccoS. LeoneA. RocaM.S. LombardiR. PiezzoM. CaputoR. CiardielloC. CostantiniS. BruzzeseF. SisalliM.J. BudillonA. De LaurentiisM. Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.J. Transl. Med.202220129010.1186/s12967‑022‑03462‑z35761360
    [Google Scholar]
  120. Tyutyunyk-MasseyL. SunY. DaoN. NgoH. DammalapatiM. VaidyanathanA. SinghM. HaqqaniS. HaueisJ. FinneganR. DengX. KirbergerS.E. BosP.D. BandyopadhyayD. PomerantzW.C.K. PommierY. GewirtzD.A. LandryJ.W. Autophagy-dependent sensitization of triple-negative breast cancer models to topoisomerase II poisons by inhibition of the nucleosome remodeling factor.Mol. Cancer Res.20211981338134910.1158/1541‑7786.MCR‑20‑074333811160
    [Google Scholar]
  121. PengX. ZhangS. JiaoW. ZhongZ. YangY. ClaretF.X. ElkabetsM. WangF. WangR. ZhongY. ChenZ-S. KongD. Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.J. Exp. Clin. Cancer Res.202140137410.1186/s13046‑021‑02176‑2
    [Google Scholar]
  122. LiZ. XuX. LiY. ZouK. ZhangZ. XuX. LiaoY. ZhaoX. JiangW. YuW. GuoW. ChenY. LiY. ChenM. DengW. LiL. ZouL. Synergistic antitumor effect of BKM120 with prima-1met via inhibiting PI3K/AKT/mTOR and CPSF4/hTERT signaling and reactivating mutant P53.Cell. Physiol. Biochem.20184551772178610.1159/00048778629495002
    [Google Scholar]
  123. WangT. SeahS. LohX. ChanC.W. HartmanM. GohB.C. LeeS.C. Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway.Oncotarget2016732532254410.18632/oncotarget.630426565813
    [Google Scholar]
  124. AlizadehJ. ZekiA.A. MirzaeiN. TewaryS. Rezaei MoghadamA. GlogowskaA. NagakannanP. EftekharpourE. WiechecE. GordonJ.W. XuF.Y. FieldJ.T. YonedaK.Y. KenyonN.J. HashemiM. HatchG.M. Hombach-KlonischS. KlonischT. GhavamiS. Mevalonate cascade inhibition by simvastatin induces the intrinsic apoptosis pathway via depletion of isoprenoids in tumor cells.Sci. Rep.2017714484110.1038/srep4484128344327
    [Google Scholar]
  125. ZhaoZ. CaoX. PanY. ShaS. ZhaoT. ZhangT. Simvastatin downregulates HER2 via upregulation of PEA3 to induce cell death in HER2-positive breast cancer cells.Oncol. Res.201220518719510.3727/096504013X1358950348269923581225
    [Google Scholar]
  126. KotamrajuS. WillamsC.L. KalyanaramanB. Statin-induced breast cancer cell death: Role of inducible nitric oxide and arginase-dependent pathways.Cancer Res.200767157386739410.1158/0008‑5472.CAN‑07‑099317671209
    [Google Scholar]
  127. GuoM. LiuM. LiW. WangC. ZhangL. ZhangH. Osteopontin promotes tumor growth and metastasis and GPX4-mediated anti-lipid peroxidation in triple-negative breast cancer by activating the PI3k/Akt/mTOR pathway.J. Cancer Res. Clin. Oncol.2024150315510.1007/s00432‑024‑05658‑w38526702
    [Google Scholar]
  128. DongC. WuJ. ChenY. NieJ. ChenC. Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer.Front. Pharmacol.20211262869010.3389/fphar.2021.62869033790792
    [Google Scholar]
  129. EdgarK.A. CrockerL. ChengE. WagleM.C. WongchenkoM. YanY. WilsonT.R. DompeN. NeveR.M. BelvinM. SampathD. FriedmanL.S. WallinJ.J. Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition.Genes Cancer201453-411312610.18632/genesandcancer.1025053989
    [Google Scholar]
  130. DerwichA. SykuteraM. BromińskaB. RubiśB. RuchałaM. Sawicka-GutajN. The role of activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in aggressive pituitary adenomas - New potential therapeutic approach - A systematic review.Int. J. Mol. Sci.202324131095210.3390/ijms24131095237446128
    [Google Scholar]
  131. CuestaC. Arévalo-AlamedaC. CastellanoE. The importance of being PI3K in the RAS signaling network.Genes (Basel)2021127109410.3390/genes1207109434356110
    [Google Scholar]
  132. WuY.Y. WuH.C. WuJ.E. HuangK.Y. YangS.C. ChenS.X. TsaoC.J. HsuK.F. ChenY.L. HongT.M. The dual PI3K/mTOR inhibitor BEZ235 restricts the growth of lung cancer tumors regardless of EGFR status, as a potent accompanist in combined therapeutic regimens.J. Exp. Clin. Cancer Res.201938128210.1186/s13046‑019‑1282‑031262325
    [Google Scholar]
  133. ParkY.L. KimH.P. ChoY.W. MinD.W. CheonS.K. LimY.J. SongS.H. KimS.J. HanS.W. ParkK.J. KimT.Y. Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations.Int. J. Cancer2019144238940110.1002/ijc.3166229978469
    [Google Scholar]
  134. TenbaumS.P. Ordóñez-MoránP. PuigI. ChicoteI. ArquésO. LandolfiS. FernándezY. HeranceJ.R. GispertJ.D. MendizabalL. AguilarS. CajalS.R. SchwartzS. VivancosA. EspínE. RojasS. BaselgaJ. TaberneroJ. MuñozA. PalmerH.G. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer.Nat. Med.201218689290110.1038/nm.277222610277
    [Google Scholar]
  135. EdwardsA. BrennanK. Notch signalling in breast development and cancer.Front. Cell Dev. Biol.2021969217310.3389/fcell.2021.69217334295896
    [Google Scholar]
  136. LiuS. KnappS. AhmedA.A. The structural basis of PI3K cancer mutations: From mechanism to therapy.Cancer Res.201474364164610.1158/0008‑5472.CAN‑13‑231924459181
    [Google Scholar]
  137. DonatiG. AmatiB. MYC and therapeuticrapy resistance in cancer: Risks and opportunities.Mol. Oncol.202216213828385410.1002/1878‑0261.1331936214609
    [Google Scholar]
  138. YuJ.S.L. CuiW. Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination.Development2016143173050306010.1242/dev.13707527578176
    [Google Scholar]
  139. ShaoY. RenW. DaiH. YangF. LiX. ZhangS. LiuJ. YaoX. ZhaoQ. SunX. ZhengZ. XuC. Skp2 contributes to AKT activation by ubiquitination degradation of PHLPP1, impedes autophagy, and facilitates the survival of thyroid carcinoma.Mol. Cells202346636037310.14348/molcells.2022.224236694914
    [Google Scholar]
  140. JinnahH. Van Den BergheG. Metabolic disorders of purine metabolism affecting the nervous system.Handbook of Clinical NeurologyElsevier2013vol. 1131827183610.1016/B978‑0‑444‑59565‑2.00052‑6
    [Google Scholar]
  141. ZhangZ. RichmondA. The role of PI3K inhibition in the treatment of breast cancer, alone or combined with immune checkpoint inhibitors.Front. Mol. Biosci.2021864866310.3389/fmolb.2021.64866334026830
    [Google Scholar]
  142. TufailM. HuJ.J. LiangJ. HeC.Y. WanW.D. HuangY.Q. JiangC.H. WuH. LiN. Predictive, preventive, and personalized medicine in breast cancer: Targeting the PI3K pathway.J. Transl. Med.20242211510.1186/s12967‑023‑04841‑w38172946
    [Google Scholar]
  143. ZardavasD. PhillipsW.A. LoiS. PIK3CA mutations in breast cancer: Reconciling findings from preclinical and clinical data.Breast Cancer Res.201416120110.1186/bcr360525192370
    [Google Scholar]
  144. SiricoM. D’AngeloA. GianniC. CasadeiC. MerloniF. De GiorgiU. Current state and future challenges for PI3K inhibitors in cancer therapy.Cancers (Basel)202315370310.3390/cancers1503070336765661
    [Google Scholar]
  145. WangY. ChenL. LiQ. GaoS. LiuS. MaJ. XieY. WangJ. CaoZ. LiuZ. Inositol polyphosphate 4-phosphatase type II Is a tumor suppressor in multiple myeloma.Front. Oncol.20221178529710.3389/fonc.2021.78529735070988
    [Google Scholar]
  146. LiuH. PaddockM.N. WangH. MurphyC.J. GeckR.C. NavarroA.J. WulfG.M. ElementoO. HauckeV. CantleyL.C. TokerA. The INPP4B tumor suppressor modulates EGFR trafficking and promotes triple-negative breast cancer.Cancer Discov.20201081226123910.1158/2159‑8290.CD‑19‑126232513774
    [Google Scholar]
  147. RodgersS.J. OomsL.M. OorschotV.M.J. SchittenhelmR.B. NguyenE.V. HamilaS.A. RynkiewiczN. GurungR. EramoM.J. SriratanaA. FedeleC.G. CaramiaF. LoiS. KerrG. AbudH.E. RammG. PapaA. EllisdonA.M. DalyR.J. McLeanC.A. MitchellC.A. INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer.Nat. Commun.2021121314010.1038/s41467‑021‑23241‑634035258
    [Google Scholar]
  148. GeorgescuM.M. PTEN tumor suppressor network in PI3K-Akt pathway control.Genes Cancer20101121170117710.1177/194760191140732521779440
    [Google Scholar]
  149. HollanderM.C. BlumenthalG.M. DennisP.A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models.Nat. Rev. Cancer201111428930110.1038/nrc303721430697
    [Google Scholar]
  150. TsayA. WangJ.C. The role of PIK3R1 in metabolic function and insulin sensitivity.Int. J. Mol. Sci.202324161266510.3390/ijms24161266537628845
    [Google Scholar]
  151. CheungL.W.T. MillsG.B. Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment.Pharmacogenomics201617329730710.2217/pgs.15.17426807692
    [Google Scholar]
/content/journals/cpd/10.2174/0113816128357976250122042633
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