Dual inhibition of PI3K and mTOR in cancer therapy: Mechanisms, clinical potential, and future perspectives
Main Article Content
Keywords
dual inhibition, PI3K-mTOR inhibitors, Targeted therapy, oncogenic pathways, molecular signaling, drug resistance
Abstract
The PI3K/AKT/mTOR signaling system is essential for controlling cell growth, survival, proliferation, and metabolism, rendering it a significant therapeutic target in cancer treatment. Dysregulation of this system is commonly reported in numerous cancers, facilitating tumor development and resistance to standard therapy. Dual inhibitors that concurrently target both Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR) provide a more thorough inhibition of this pathway, reducing the deficiencies of single-agent inhibitors and bypassing compensatory mechanisms that frequently result in therapeutic resistance. This review investigates the molecular basis of dual PI3K/mTOR inhibition, emphasizing its potential to improve cancer treatment effects. We provide a concise overview of the preclinical and clinical data that substantiates the efficacy of dual inhibitors in various malignancies, including breast, prostate, colorectal, pancreatic, ovarian, and lung cancers. Significant antitumor activity has been demonstrated by notable dual inhibitors when combined with chemotherapy or targeted agents. However, challenges such as resistance and toxicity persist. Additional research is required to refine dose protocols, optimize patient selection by biomarker identification, and investigate combination drugs to improve efficacy while reducing undesirable effects. The advancement of nanoformulations has demonstrated potential in enhancing medicine delivery and reducing systemic toxicity. Dual PI3K/mTOR inhibitors constitute a promising therapeutic strategy, providing significant enhancements in tailored cancer treatment, particularly for individuals with resistant or aggressive malignancies.
References
1. Dakilah I, Harb A, Abu-Gharbieh E, et al. Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine. Front Pharmacol. 2024;15.10.3389/fphar.2024.1324001.
2. El Dakkak B, Taneera J, El-Huneidi W, et al. Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy. Biomol Ther. 2024;32(3):267-280.10.4062/biomolther.2023.149.
3. Qannita RA, Alalami AI, Harb AA, et al. Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation. Pharmaceuticals. 2024;17(2).10.3390/ph17020195.
4. Sirajudeen F, Bou Malhab LJ, Bustanji Y, et al. Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives. Biomol Ther. 2024;32(1):38-55.10.4062/biomolther.2023.054.
5. Tufail M, Wan WD, Jiang C, Li N. Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer. Chem-Biol Interact. 2024;396.10.1016/j.cbi.2024.111055.
6. Zhang HP, Jiang RY, Zhu JY, et al. PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer. Breast Cancer. 2024;31(4):539-551.10.1007/s12282-024-01567-5.
7. Armando I, Cuevas S, Fan C, et al. G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells. Int J Mol Sci. 2022;23(22).10.3390/ijms232214456.
8. Rathinaswamy MK, Jenkins ML, Duewell BR, et al. Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs. Cell Rep. 2023;42(3).10.1016/j.celrep.2023.112172.
9. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol Cancer. 2019;18(1).10.1186/s12943-019-0954-x.
10. Li F, Hu G, Long X, et al. Stearic Acid Activates the PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 Signaling Axes through FATP4-CDK1 to Promote Milk Synthesis in Primary Bovine Mammary Epithelial Cells. J Agric Food Chem. 2022;70(13):4007-4018.10.1021/acs.jafc.2c00208.
11. Luo L, Sun X, Yang Y, et al. A Novel Dual PI3K/mTOR Inhibitor, XIN-10, for the Treatment of Cancer. Int J Mol Sci. 2023;24(19).10.3390/ijms241914821.
12. Wu X, Xu Y, Liang Q, et al. Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment. Front Pharmacol. 2022;13.10.3389/fphar.2022.875372.
13. Alimohammadi M, Rahimzadeh P, Khorrami R, et al. A comprehensive review of the PTEN/PI3K/Akt axis in multiple myeloma: From molecular interactions to potential therapeutic targets. Pathol Res Pract. 2024;260.10.1016/j.prp.2024.155401.
14. Sadrkhanloo M, Paskeh MDA, Hashemi M, et al. New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis. Pathol Res Pract. 2023;251.10.1016/j.prp.2023.154902.
15. Bou Malhab LJ, Harb AA, ElDohaji L, et al. Exploring the Anticancer Effect of Artemisia herba-alba on Colorectal Cancer: Insights From Eight Colorectal Cancer Cell Lines. Food Sci Nutr. 2025;13(1).Doi:10.1002/fsn3.4715.
16. Sirico M, D’Angelo A, Gianni C, Casadei C, Merloni F, De Giorgi U. Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers. 2023;15(3).10.3390/cancers15030703.
17. Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1).10.1186/s12943-023-01827-6.
18. Murase Y, Hosoya K, Sato T, Kim S, Okumura M. Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells. Oncol Rep. 2022;47(4).10.3892/or.2022.8272.
19. Hong DS, Moore KN, Bendell JC, et al. Preclinical evaluation and phase ib study of prexasertib, a chk1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor. Clin Cancer Res. 2021;27(7):1864-1874.10.1158/1078-0432.CCR-20-3242.
20. Chen M, Lan H, Yao S, Jin K, Chen Y. Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors. Cancers. 2023;15(7).10.3390/cancers15072043.
21. Jain S, Gupta SP. Cancer Therapy with Quinoxaline Derivatives: Dual Inhibition of Pi3k and Mtor Signaling Pathways. Res J Pharm Technol. 2024;17(8):4068-4074.10.52711/0974-360X.2024.00631.
22. Cerma K, Piacentini F, Moscetti L, et al. Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges. Biomedicines. 2023;11(1).10.3390/biomedicines11010109.
23. Janku F, Choong GM, Opyrchal M, et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers. 2024;16(6).10.3390/cancers16061137.
24. Geuna E, Roda D, Rafii S, et al. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials. Br J Cancer. 2015;113(11):1541-1547.10.1038/bjc.2015.373.
25. Khan KH, Wong M, Rihawi K, et al. Hyperglycemia and phosphatidylinositol 3-kinase/protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) Inhibitors in phase I trials: Incidence, predictive factors, and management. Oncologist. 2016;21(7):855-860.10.1634/theoncologist.2015-0248.
26. Bos S, De Sadeleer LJ, Yserbyt J, et al. Real life experience with mTOR-inhibitors after lung transplantation. Int Immunopharmacol. 2021;94.10.1016/j.intimp.2021.107501.
27. Ali ES, Mitra K, Akter S, et al. Recent advances and limitations of mTOR inhibitors in the treatment of cancer. Cancer Cell Int. 2022;22(1).10.1186/s12935-022-02706-8.
28. Huang Y, Xue X, Li X, et al. Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration-Resistant Prostate Cancer. Adv Ther. 2020;3(10).10.1002/adtp.202000075.
29. Wang M, Li L, Zhong W, et al. Synergistic anti-osteosarcoma cell effects of the methotrexate/PI3K/mTOR inhibitor nanoparticle codelivery system. Mater Technol. 2024;39(1).10.1080/10667857.2024.2362572.
30. Hamad I, Harb AA, Bustanji Y. Liposome-Based Drug Delivery Systems in Cancer Research: An Analysis of Global Landscape Efforts and Achievements. Pharmaceutics. 2024;16(3).10.3390/pharmaceutics16030400.
31. Matalqah SM, Aiedeh K, Mhaidat NM, Alzoubi KH, Bustanji Y, Hamad I. Chitosan nanoparticles as a novel drug delivery system: A review article. Curr Drug Targets. 2020;21(15):1613-1624.10.2174/1389450121666200711172536.
32. Han X, Mei Y, Mishra RK, et al. Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models. J Clin Invest. 2023;133(6).10.1172/JCI159638.
33. Lee SL, Chou CC, Chuang HC, et al. Functional Role of mTORC2 versus Integrin-Linked Kinase in Mediating Ser473-Akt Phosphorylation in PTEN-Negative Prostate and Breast Cancer Cell Lines. PLoS ONE. 2013;8(6).10.1371/journal.pone.0067149.
34. Thoa NT, Son NT. Scutellarein: a review of chemistry and pharmacology. J Pharm Pharmacol. 2025;77(3):352-370.Doi:10.1093/jpp/rgae039.
35. Li H, Wen X, Ren Y, et al. Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions. Mol Cancer. 2024;23(1).10.1186/s12943-024-02072-1.
36. Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023). Expert Opin Ther Pat. 2024;34(3):141-158.10.1080/13543776.2024.2338100.
37. Zhang Y, Xu X, Yang K, et al. The efficacy and safety of PI3K and AKT inhibitors for patients with cancer: A systematic review and network meta-analysis. Eur J Pharmacol. 2024;983.10.1016/j.ejphar.2024.176952.
38. Al-Hawary SIS, Altalbawy FMA, Jasim SA, et al. Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis. Cell Biol Int. 2024;48(11):1601-1611.10.1002/cbin.12231.
39. Walters HE, Cox LS. mTORC inhibitors as broad-spectrum therapeutics for age-related diseases. Int J Mol Sci. 2018;19(8).10.3390/ijms19082325.
40. Gao H, Zhang J, Ren X. PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling. Biosci Rep. 2019;39(12).10.1042/BSR20191041.
41. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy. 2011;7(7):737-747.10.4161/auto.7.7.15491.
42. Yoon MS, Sun Y, Arauz E, Jiang Y, Chen J. Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem. 2011;286(34):29568-29574.10.1074/jbc.M111.262816.
43. Melick CH, Jewell JL. Small molecule H89 renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors. Biochem J. 2020;447(10):1847-1863.10.1042/BCJ20190958.
44. Saran U, Foti M, Dufour JF. Cellular and molecular effects of the mTOR inhibitor everolimus. Clin Sci. 2015;129(10):895-914.10.1042/CS20150149.
45. Vernieri C, Corti F, Nichetti F, et al. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: Targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications. Breast Cancer Res. 2020;22(1).10.1186/s13058-020-01271-0.
46. Smolewski P, Rydygier D. Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies. Expert Opin Pharmacother. 2020:1915-1926.10.1080/14656566.2020.1791083.
47. Shi F, Zhang J, Liu H, et al. The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. Oncotarget. 2018;9(1):706-717.10.18632/oncotarget.23091.
48. Sweeney CJ, Percent IJ, Babu S, et al. Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022;28(11):2237-2247.10.1158/1078-0432.CCR-21-2326.
49. Curigliano G, Martin M, Jhaveri K, et al. Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study. Eur J Cancer. 2021;151:49-62.10.1016/j.ejca.2021.03.042.
50. Gao H, Li Z, Wang K, et al. Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors. Pharmaceuticals. 2023;16(3).10.3390/ph16030461.
51. He R, Xu B, Ping L, Lv X. Structural optimization towards promising β-methyl-4-acrylamido quinoline derivatives as PI3K/mTOR dual inhibitors for anti-cancer therapy: The in vitro and in vivo biological evaluation. Eur J Med Chem. 2021;214.10.1016/j.ejmech.2021.113249.
52. Basu D, Salgado CM, Bauer B, et al. The dual PI3K/mToR inhibitor omipalisib/GSK2126458 inhibits clonogenic growth in oncogenically-transformed cells from neurocutaneous melanocytosis. Cancer Genomics Proteomics. 2018;15(4):239-248.10.21873/cgp.20082.
53. Finlay MRV, Buttar D, Critchlow SE, et al. Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor. Bioorg Med Chem Lett. 2012;22(12):4163-4168.10.1016/j.bmcl.2012.04.036.
54. Schoen LF, Craveiro RB, Pietsch T, et al. The PI3K inhibitor pictilisib and the multikinase inhibitors pazopanib and sorafenib have an impact on Rac1 level and migration of medulloblastoma in vitro. J Cell Mol Med. 2022;26(23):5832-5845.10.1111/jcmm.17604.
55. Kasabri V, Afifi FU, Abu-Dahab R, et al. In vitro modulation of metabolic syndrome enzymes and proliferation of obesity related-colorectal cancer cell line panel by salvia species from jordan. Rev Roumaine Chim. 2014;59(8):693-705.
56. Rattis BAC, Piva HL, Duarte A, et al. Modulation of the mTOR Pathway by Curcumin in the Heart of Septic Mice. Pharmaceutics. 2022;14(11).10.3390/pharmaceutics14112277.
57. Nugraha AP, Yudianto DO, Anwar AA, et al. Potential of Curcumin-Quercetin Loaded Nanostructured Lipid Carriers as Oral Squamous Cell Carcinoma Adjuvant Therapy by Downregulating AKT/PI3K Signaling Pathway. Res J Pharm Technol. 2022;15(11):5353-5358.10.52711/0974-360X.2022.00902.
58. Bian P, Hu W, Liu C, Li L. Resveratrol potentiates the anti-tumor effects of rapamycin in papillary thyroid cancer: PI3K/AKT/mTOR pathway involved. Arch Biochem Biophys. 2020;689.10.1016/j.abb.2020.108461.
59. Widlund AL, Baur JA, Vang O. mTOR: more targets of resveratrol? Expert Rev Mol Med. 2013;15:e10.10.1017/erm.2013.11.
60. Satonaka H, Ishida K, Takai M, et al. (-)-Epigallocatechin-3-gallate down-regulates doxorubicin-induced overexpression of P-glycoprotein through the coordinate inhibition of PI3K/Akt and MEK/ERK signaling pathways. Anticancer Res. 2017;37(11):6071-6077.10.21873/anticanres.12055.
61. Liu J, Liu P, Xu T, et al. Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling. Drug Des Devel Ther. 2020;14:1813-1823.10.2147/DDDT.S239247.
62. Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 2010;31(8):1424-1433.10.1093/carcin/bgq115.
63. Pothongsrisit S, Pongrakhananon V. Targeting the pi3k/akt/mtor signaling pathway in lung cancer: An update regarding potential drugs and natural products. Molecules. 2021;26(13).10.3390/molecules26134100.
64. AlKhatib HS, Taha MO, Aiedeh KM, Bustanji Y, Sweileh B. Synthesis and in vitro behavior of iron-crosslinked N-methyl and N-benzyl hydroxamated derivatives of alginic acid as controlled release carriers. Eur Polym J. 2006;42(10):2464-2474.10.1016/j.eurpolymj.2006.05.018.
65. Gharaibeh L, Alshaer W, Wehaibi S, et al. Fabrication of aptamer-guided siRNA loaded lipopolyplexes for gene silencing of notch 1 in MDA-mb-231 triple negative breast cancer cell line. J Drug Deliv Sci Technol. 2021;65.10.1016/j.jddst.2021.102733.
66. Lafi Z, Alshaer W, Hatmal MM, et al. Aptamer-functionalized pH-sensitive liposomes for a selective delivery of echinomycin into cancer cells. RSC Adv. 2021;11(47):29164-29177.10.1039/d1ra05138e.
67. Zhang YC, Wu CG, Li AM, Liang Y, Ma D, Tang XL. Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy. J Biomed Nanotechnol. 2021;17(1):18-36.10.1166/jbn.2021.3014.
68. Gholizadeh S, Kamps JAAM, Hennink WE, Kok RJ. PLGA-PEG nanoparticles for targeted delivery of the mTOR/PI3kinase inhibitor dactolisib to inflamed endothelium. Int J Pharm. 2018;548(2):747-758.10.1016/j.ijpharm.2017.10.032.
69. Fan F, Tan D, Shang S, et al. Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) Biopolyester Based Nanoparticles as NVP-BEZ235 Delivery Vehicle for Tumor Targeting Therapy. Biomacromolecules. 2019;20(9):3313-3323.10.1021/acs.biomac.9b00505.
70. Sen A, Khan S, Rossetti S, et al. Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway. Mol Oncol. 2025;19(1):225-247.10.1002/1878-0261.13703.
71. Tian L, Wang L, Qiao Y, et al. Antitumor effcacy of liposome-encapsulated NVP-BEZ235 combined with irreversible electroporation for head and neck cancer. Molecules. 2019;24(19).10.3390/molecules24193560.
72. Shi H, van Steenbergen MJ, Lou B, Liu Y, Hennink WE, Kok RJ. Folate decorated polymeric micelles for targeted delivery of the kinase inhibitor dactolisib to cancer cells. Int J Pharm. 2020;582.10.1016/j.ijpharm.2020.119305.
73. Luo L, Zhong Q, Guo S, et al. Development of a bioavailable boron-containing PI-103 Bioisostere, PI-103BE. Bioorg Med Chem Lett. 2020;30(14).10.1016/j.bmcl.2020.127258.
74. Maurya AK, Vinayak M. PI-103 attenuates PI3K-AKT signaling and induces apoptosis in murine T-cell lymphoma. Leuk Lymphoma. 2017;58(5):1153-1161.10.1080/10428194.2016.1225207.
75. Liu Y, Sun Q, Wei X. Strategies and techniques for preclinical therapeutic targeting of PI3K in oncology: where do we stand in 2024? Expert Opin Ther Targets. 2024;28(3):221-232.10.1080/14728222.2024.2342522.
76. Chaudhuri A, Kumar DN, Dehari D, et al. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC). Pharmaceuticals. 2022;15(5).10.3390/ph15050542.
77. Zhao B, Lei F, Wang C, et al. Design, synthesis and biological evaluation of novel phenylsulfonylurea derivatives as PI3K/mTOR dual inhibitors. Molecules. 2018;23(7).10.3390/molecules23071553.
78. Diab SE, Tayea NA, Elwakil BH, et al. In vitro and in vivo anti-colorectal cancer effect of the newly synthesized sericin/propolis/fluorouracil nanoplatform through modulation of PI3K/AKT/mTOR pathway. Sci Rep. 2024;14(1).10.1038/s41598-024-52722-z.
79. Wang L, Wang Y, Xie Q, et al. Resveratrol liposomes reverse sorafenib resistance in renal cell carcinoma models by modulating PI3K-AKT-mTOR and VHL-HIF signaling pathways. Int J Pharm X. 2024;8.10.1016/j.ijpx.2024.100280.
80. Jin L, Zhang W, Yao MY, Tian Y, Xue BX, Tao W. GNE-493 inhibits prostate cancer cell growth via Akt-mTOR-dependent and -independent mechanisms. Cell Death Discov. 2022;8(1).10.1038/s41420-022-00911-y.
81. Youssef M, Moussa N, W. Helmy M, Haroun M. Unraveling the therapeutic potential of GANT61/Dactolisib combination as a novel prostate cancer modality. Med Oncol. 2022;39(10).10.1007/s12032-022-01718-8.
82. Feng Y, Jiang Y, Hao F. GSK2126458 has the potential to inhibit the proliferation of pancreatic cancer uncovered by bioinformatics analysis and pharmacological experiments. J Transl Med. 2021;19(1).10.1186/s12967-021-03050-7.
83. Wise-Draper TM, Moorthy G, Salkeni MA, et al. A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Targeted Oncol. 2017;12(3):323-332.10.1007/s11523-017-0482-9.
84. Shang X, Na X, Wang L, Yang Z, Ren P. Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells. Evid-Based Complement Altern Med. 2022;2022.10.1155/2022/8110796.
85. Prat A, Brase JC, Cheng Y, et al. Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2. Oncologist. 2019;24(7):893-900.10.1634/theoncologist.2018-0407.
86. Layman RM, Han HS, Rugo HS, et al. Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study. Lancet Oncol. 2024;25(4):474-487.10.1016/S1470-2045(24)00034-2.
87. Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer. Drugs. 2020;80(16):1685-1697.10.1007/s40265-020-01394-w.
88. Dunn E, Chitcholtan K, Sykes P, Garrill A. The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models. Cancers. 2022;14(2).10.3390/cancers14020395.
89. Liu T, Sun Q, Li Q, et al. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther. 2015;14(2):429-439.10.1158/1535-7163.MCT-14-0548.
90. Valdez BC, Yuan B, Murray D, Nieto Y, Popat U, Andersson BS. Enhanced cytotoxicity of bisantrene when combined with venetoclax, panobinostat, decitabine and olaparib in acute myeloid leukemia cells. Leuk Lymphoma. 2022;63(7):1634-1644.10.1080/10428194.2022.2042689.
91. Philip CA, Laskov I, Beauchamp MC, et al. Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer. 2017;17(1).10.1186/s12885-017-3639-0.
92. Langdon SP, Kay C, Um IH, et al. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci Rep. 2019;9(1).10.1038/s41598-019-55096-9.
93. Wu YY, Wu HC, Wu JE, et al. 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. 2019;38(1).10.1186/s13046-019-1282-0.
94. Wang R, Li A, Liu J, et al. BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells. J Chemother. 2023;35(2):95-103.10.1080/1120009X.2022.2045826.
95. Wainberg ZA, Alsina M, Soares HP, et al. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Targeted Oncol. 2017;12(6):775-785.10.1007/s11523-017-0530-5.
96. Grilley-Olson JE, Bedard PL, Fasolo A, et al. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Invest New Drugs. 2016;34(6):740-749.10.1007/s10637-016-0377-0.
97. Leiphrakpam PD, Are C. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. Int J Mol Sci. 2024;25(6).10.3390/ijms25063178.
98. Zhang S, Zhu X, Gao L, et al. Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors. Journal of Clinical Oncology. 06/01 2024;42:e14627-e14627.10.1200/JCO.2024.42.16_suppl.e14627.
99. Guo Y, Xue L, Tang W, et al. 874P Preliminary outcomes from a phase Ib/II study of WX390 combined with toripalimab in patients with recurrent or metastatic head and neck squamous cell carcinoma. Annals of Oncology. 2024;35:S626.10.1016/j.annonc.2024.08.935.
100. Desravines N, Tran C, Wethington S, Williams-Brown MY. Contemporary Review of Adenocarcinoma of the Cervix. Curr Treat Options Oncol. 2024;25(12):1538-1549.10.1007/s11864-024-01254-9.
101. Zheng K, Jin G, Cao R, et al. Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma. Cancer Chemother Pharmacol. 2025;95(1).10.1007/s00280-024-04748-3.
102. Hossain MT, Hossain MA. Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes. Eur J Pharmacol. 2025;996.10.1016/j.ejphar.2025.177432.
103. Gunder LC, Moyer TH, Johnson HR, et al. Anal Cancer Prevention Through the Topical Use of Single or Dual PI3K/mTOR Inhibitors. J Surg Res. 2023;282:137-146.10.1016/j.jss.2022.09.025.
104. Janku F, Choong GM, Opyrchal M, et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers (Basel). Mar 13 2024;16(6).10.3390/cancers16061137.
105. Mardanshahi A, Gharibkandi NA, Vaseghi S, Abedi SM, Molavipordanjani S. The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines. Mol Biol Rep. 2021;48(8).10.1007/s11033-021-06607-3.
106. Wallin JJ, Edgar KA, Guan J, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011;10(12):2426-2436.10.1158/1535-7163.MCT-11-0446.
107. Mortazavi M, Moosavi F, Martini M, Giovannetti E, Firuzi O. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer. Crit Rev Oncol Hematol. 2022;176.10.1016/j.critrevonc.2022.103749.
2. El Dakkak B, Taneera J, El-Huneidi W, et al. Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy. Biomol Ther. 2024;32(3):267-280.10.4062/biomolther.2023.149.
3. Qannita RA, Alalami AI, Harb AA, et al. Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation. Pharmaceuticals. 2024;17(2).10.3390/ph17020195.
4. Sirajudeen F, Bou Malhab LJ, Bustanji Y, et al. Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives. Biomol Ther. 2024;32(1):38-55.10.4062/biomolther.2023.054.
5. Tufail M, Wan WD, Jiang C, Li N. Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer. Chem-Biol Interact. 2024;396.10.1016/j.cbi.2024.111055.
6. Zhang HP, Jiang RY, Zhu JY, et al. PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer. Breast Cancer. 2024;31(4):539-551.10.1007/s12282-024-01567-5.
7. Armando I, Cuevas S, Fan C, et al. G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells. Int J Mol Sci. 2022;23(22).10.3390/ijms232214456.
8. Rathinaswamy MK, Jenkins ML, Duewell BR, et al. Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs. Cell Rep. 2023;42(3).10.1016/j.celrep.2023.112172.
9. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol Cancer. 2019;18(1).10.1186/s12943-019-0954-x.
10. Li F, Hu G, Long X, et al. Stearic Acid Activates the PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 Signaling Axes through FATP4-CDK1 to Promote Milk Synthesis in Primary Bovine Mammary Epithelial Cells. J Agric Food Chem. 2022;70(13):4007-4018.10.1021/acs.jafc.2c00208.
11. Luo L, Sun X, Yang Y, et al. A Novel Dual PI3K/mTOR Inhibitor, XIN-10, for the Treatment of Cancer. Int J Mol Sci. 2023;24(19).10.3390/ijms241914821.
12. Wu X, Xu Y, Liang Q, et al. Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment. Front Pharmacol. 2022;13.10.3389/fphar.2022.875372.
13. Alimohammadi M, Rahimzadeh P, Khorrami R, et al. A comprehensive review of the PTEN/PI3K/Akt axis in multiple myeloma: From molecular interactions to potential therapeutic targets. Pathol Res Pract. 2024;260.10.1016/j.prp.2024.155401.
14. Sadrkhanloo M, Paskeh MDA, Hashemi M, et al. New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis. Pathol Res Pract. 2023;251.10.1016/j.prp.2023.154902.
15. Bou Malhab LJ, Harb AA, ElDohaji L, et al. Exploring the Anticancer Effect of Artemisia herba-alba on Colorectal Cancer: Insights From Eight Colorectal Cancer Cell Lines. Food Sci Nutr. 2025;13(1).Doi:10.1002/fsn3.4715.
16. Sirico M, D’Angelo A, Gianni C, Casadei C, Merloni F, De Giorgi U. Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers. 2023;15(3).10.3390/cancers15030703.
17. Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1).10.1186/s12943-023-01827-6.
18. Murase Y, Hosoya K, Sato T, Kim S, Okumura M. Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells. Oncol Rep. 2022;47(4).10.3892/or.2022.8272.
19. Hong DS, Moore KN, Bendell JC, et al. Preclinical evaluation and phase ib study of prexasertib, a chk1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor. Clin Cancer Res. 2021;27(7):1864-1874.10.1158/1078-0432.CCR-20-3242.
20. Chen M, Lan H, Yao S, Jin K, Chen Y. Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors. Cancers. 2023;15(7).10.3390/cancers15072043.
21. Jain S, Gupta SP. Cancer Therapy with Quinoxaline Derivatives: Dual Inhibition of Pi3k and Mtor Signaling Pathways. Res J Pharm Technol. 2024;17(8):4068-4074.10.52711/0974-360X.2024.00631.
22. Cerma K, Piacentini F, Moscetti L, et al. Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges. Biomedicines. 2023;11(1).10.3390/biomedicines11010109.
23. Janku F, Choong GM, Opyrchal M, et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers. 2024;16(6).10.3390/cancers16061137.
24. Geuna E, Roda D, Rafii S, et al. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials. Br J Cancer. 2015;113(11):1541-1547.10.1038/bjc.2015.373.
25. Khan KH, Wong M, Rihawi K, et al. Hyperglycemia and phosphatidylinositol 3-kinase/protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) Inhibitors in phase I trials: Incidence, predictive factors, and management. Oncologist. 2016;21(7):855-860.10.1634/theoncologist.2015-0248.
26. Bos S, De Sadeleer LJ, Yserbyt J, et al. Real life experience with mTOR-inhibitors after lung transplantation. Int Immunopharmacol. 2021;94.10.1016/j.intimp.2021.107501.
27. Ali ES, Mitra K, Akter S, et al. Recent advances and limitations of mTOR inhibitors in the treatment of cancer. Cancer Cell Int. 2022;22(1).10.1186/s12935-022-02706-8.
28. Huang Y, Xue X, Li X, et al. Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration-Resistant Prostate Cancer. Adv Ther. 2020;3(10).10.1002/adtp.202000075.
29. Wang M, Li L, Zhong W, et al. Synergistic anti-osteosarcoma cell effects of the methotrexate/PI3K/mTOR inhibitor nanoparticle codelivery system. Mater Technol. 2024;39(1).10.1080/10667857.2024.2362572.
30. Hamad I, Harb AA, Bustanji Y. Liposome-Based Drug Delivery Systems in Cancer Research: An Analysis of Global Landscape Efforts and Achievements. Pharmaceutics. 2024;16(3).10.3390/pharmaceutics16030400.
31. Matalqah SM, Aiedeh K, Mhaidat NM, Alzoubi KH, Bustanji Y, Hamad I. Chitosan nanoparticles as a novel drug delivery system: A review article. Curr Drug Targets. 2020;21(15):1613-1624.10.2174/1389450121666200711172536.
32. Han X, Mei Y, Mishra RK, et al. Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models. J Clin Invest. 2023;133(6).10.1172/JCI159638.
33. Lee SL, Chou CC, Chuang HC, et al. Functional Role of mTORC2 versus Integrin-Linked Kinase in Mediating Ser473-Akt Phosphorylation in PTEN-Negative Prostate and Breast Cancer Cell Lines. PLoS ONE. 2013;8(6).10.1371/journal.pone.0067149.
34. Thoa NT, Son NT. Scutellarein: a review of chemistry and pharmacology. J Pharm Pharmacol. 2025;77(3):352-370.Doi:10.1093/jpp/rgae039.
35. Li H, Wen X, Ren Y, et al. Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions. Mol Cancer. 2024;23(1).10.1186/s12943-024-02072-1.
36. Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023). Expert Opin Ther Pat. 2024;34(3):141-158.10.1080/13543776.2024.2338100.
37. Zhang Y, Xu X, Yang K, et al. The efficacy and safety of PI3K and AKT inhibitors for patients with cancer: A systematic review and network meta-analysis. Eur J Pharmacol. 2024;983.10.1016/j.ejphar.2024.176952.
38. Al-Hawary SIS, Altalbawy FMA, Jasim SA, et al. Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis. Cell Biol Int. 2024;48(11):1601-1611.10.1002/cbin.12231.
39. Walters HE, Cox LS. mTORC inhibitors as broad-spectrum therapeutics for age-related diseases. Int J Mol Sci. 2018;19(8).10.3390/ijms19082325.
40. Gao H, Zhang J, Ren X. PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling. Biosci Rep. 2019;39(12).10.1042/BSR20191041.
41. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy. 2011;7(7):737-747.10.4161/auto.7.7.15491.
42. Yoon MS, Sun Y, Arauz E, Jiang Y, Chen J. Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem. 2011;286(34):29568-29574.10.1074/jbc.M111.262816.
43. Melick CH, Jewell JL. Small molecule H89 renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors. Biochem J. 2020;447(10):1847-1863.10.1042/BCJ20190958.
44. Saran U, Foti M, Dufour JF. Cellular and molecular effects of the mTOR inhibitor everolimus. Clin Sci. 2015;129(10):895-914.10.1042/CS20150149.
45. Vernieri C, Corti F, Nichetti F, et al. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: Targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications. Breast Cancer Res. 2020;22(1).10.1186/s13058-020-01271-0.
46. Smolewski P, Rydygier D. Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies. Expert Opin Pharmacother. 2020:1915-1926.10.1080/14656566.2020.1791083.
47. Shi F, Zhang J, Liu H, et al. The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. Oncotarget. 2018;9(1):706-717.10.18632/oncotarget.23091.
48. Sweeney CJ, Percent IJ, Babu S, et al. Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022;28(11):2237-2247.10.1158/1078-0432.CCR-21-2326.
49. Curigliano G, Martin M, Jhaveri K, et al. Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study. Eur J Cancer. 2021;151:49-62.10.1016/j.ejca.2021.03.042.
50. Gao H, Li Z, Wang K, et al. Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors. Pharmaceuticals. 2023;16(3).10.3390/ph16030461.
51. He R, Xu B, Ping L, Lv X. Structural optimization towards promising β-methyl-4-acrylamido quinoline derivatives as PI3K/mTOR dual inhibitors for anti-cancer therapy: The in vitro and in vivo biological evaluation. Eur J Med Chem. 2021;214.10.1016/j.ejmech.2021.113249.
52. Basu D, Salgado CM, Bauer B, et al. The dual PI3K/mToR inhibitor omipalisib/GSK2126458 inhibits clonogenic growth in oncogenically-transformed cells from neurocutaneous melanocytosis. Cancer Genomics Proteomics. 2018;15(4):239-248.10.21873/cgp.20082.
53. Finlay MRV, Buttar D, Critchlow SE, et al. Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor. Bioorg Med Chem Lett. 2012;22(12):4163-4168.10.1016/j.bmcl.2012.04.036.
54. Schoen LF, Craveiro RB, Pietsch T, et al. The PI3K inhibitor pictilisib and the multikinase inhibitors pazopanib and sorafenib have an impact on Rac1 level and migration of medulloblastoma in vitro. J Cell Mol Med. 2022;26(23):5832-5845.10.1111/jcmm.17604.
55. Kasabri V, Afifi FU, Abu-Dahab R, et al. In vitro modulation of metabolic syndrome enzymes and proliferation of obesity related-colorectal cancer cell line panel by salvia species from jordan. Rev Roumaine Chim. 2014;59(8):693-705.
56. Rattis BAC, Piva HL, Duarte A, et al. Modulation of the mTOR Pathway by Curcumin in the Heart of Septic Mice. Pharmaceutics. 2022;14(11).10.3390/pharmaceutics14112277.
57. Nugraha AP, Yudianto DO, Anwar AA, et al. Potential of Curcumin-Quercetin Loaded Nanostructured Lipid Carriers as Oral Squamous Cell Carcinoma Adjuvant Therapy by Downregulating AKT/PI3K Signaling Pathway. Res J Pharm Technol. 2022;15(11):5353-5358.10.52711/0974-360X.2022.00902.
58. Bian P, Hu W, Liu C, Li L. Resveratrol potentiates the anti-tumor effects of rapamycin in papillary thyroid cancer: PI3K/AKT/mTOR pathway involved. Arch Biochem Biophys. 2020;689.10.1016/j.abb.2020.108461.
59. Widlund AL, Baur JA, Vang O. mTOR: more targets of resveratrol? Expert Rev Mol Med. 2013;15:e10.10.1017/erm.2013.11.
60. Satonaka H, Ishida K, Takai M, et al. (-)-Epigallocatechin-3-gallate down-regulates doxorubicin-induced overexpression of P-glycoprotein through the coordinate inhibition of PI3K/Akt and MEK/ERK signaling pathways. Anticancer Res. 2017;37(11):6071-6077.10.21873/anticanres.12055.
61. Liu J, Liu P, Xu T, et al. Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling. Drug Des Devel Ther. 2020;14:1813-1823.10.2147/DDDT.S239247.
62. Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 2010;31(8):1424-1433.10.1093/carcin/bgq115.
63. Pothongsrisit S, Pongrakhananon V. Targeting the pi3k/akt/mtor signaling pathway in lung cancer: An update regarding potential drugs and natural products. Molecules. 2021;26(13).10.3390/molecules26134100.
64. AlKhatib HS, Taha MO, Aiedeh KM, Bustanji Y, Sweileh B. Synthesis and in vitro behavior of iron-crosslinked N-methyl and N-benzyl hydroxamated derivatives of alginic acid as controlled release carriers. Eur Polym J. 2006;42(10):2464-2474.10.1016/j.eurpolymj.2006.05.018.
65. Gharaibeh L, Alshaer W, Wehaibi S, et al. Fabrication of aptamer-guided siRNA loaded lipopolyplexes for gene silencing of notch 1 in MDA-mb-231 triple negative breast cancer cell line. J Drug Deliv Sci Technol. 2021;65.10.1016/j.jddst.2021.102733.
66. Lafi Z, Alshaer W, Hatmal MM, et al. Aptamer-functionalized pH-sensitive liposomes for a selective delivery of echinomycin into cancer cells. RSC Adv. 2021;11(47):29164-29177.10.1039/d1ra05138e.
67. Zhang YC, Wu CG, Li AM, Liang Y, Ma D, Tang XL. Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy. J Biomed Nanotechnol. 2021;17(1):18-36.10.1166/jbn.2021.3014.
68. Gholizadeh S, Kamps JAAM, Hennink WE, Kok RJ. PLGA-PEG nanoparticles for targeted delivery of the mTOR/PI3kinase inhibitor dactolisib to inflamed endothelium. Int J Pharm. 2018;548(2):747-758.10.1016/j.ijpharm.2017.10.032.
69. Fan F, Tan D, Shang S, et al. Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) Biopolyester Based Nanoparticles as NVP-BEZ235 Delivery Vehicle for Tumor Targeting Therapy. Biomacromolecules. 2019;20(9):3313-3323.10.1021/acs.biomac.9b00505.
70. Sen A, Khan S, Rossetti S, et al. Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway. Mol Oncol. 2025;19(1):225-247.10.1002/1878-0261.13703.
71. Tian L, Wang L, Qiao Y, et al. Antitumor effcacy of liposome-encapsulated NVP-BEZ235 combined with irreversible electroporation for head and neck cancer. Molecules. 2019;24(19).10.3390/molecules24193560.
72. Shi H, van Steenbergen MJ, Lou B, Liu Y, Hennink WE, Kok RJ. Folate decorated polymeric micelles for targeted delivery of the kinase inhibitor dactolisib to cancer cells. Int J Pharm. 2020;582.10.1016/j.ijpharm.2020.119305.
73. Luo L, Zhong Q, Guo S, et al. Development of a bioavailable boron-containing PI-103 Bioisostere, PI-103BE. Bioorg Med Chem Lett. 2020;30(14).10.1016/j.bmcl.2020.127258.
74. Maurya AK, Vinayak M. PI-103 attenuates PI3K-AKT signaling and induces apoptosis in murine T-cell lymphoma. Leuk Lymphoma. 2017;58(5):1153-1161.10.1080/10428194.2016.1225207.
75. Liu Y, Sun Q, Wei X. Strategies and techniques for preclinical therapeutic targeting of PI3K in oncology: where do we stand in 2024? Expert Opin Ther Targets. 2024;28(3):221-232.10.1080/14728222.2024.2342522.
76. Chaudhuri A, Kumar DN, Dehari D, et al. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC). Pharmaceuticals. 2022;15(5).10.3390/ph15050542.
77. Zhao B, Lei F, Wang C, et al. Design, synthesis and biological evaluation of novel phenylsulfonylurea derivatives as PI3K/mTOR dual inhibitors. Molecules. 2018;23(7).10.3390/molecules23071553.
78. Diab SE, Tayea NA, Elwakil BH, et al. In vitro and in vivo anti-colorectal cancer effect of the newly synthesized sericin/propolis/fluorouracil nanoplatform through modulation of PI3K/AKT/mTOR pathway. Sci Rep. 2024;14(1).10.1038/s41598-024-52722-z.
79. Wang L, Wang Y, Xie Q, et al. Resveratrol liposomes reverse sorafenib resistance in renal cell carcinoma models by modulating PI3K-AKT-mTOR and VHL-HIF signaling pathways. Int J Pharm X. 2024;8.10.1016/j.ijpx.2024.100280.
80. Jin L, Zhang W, Yao MY, Tian Y, Xue BX, Tao W. GNE-493 inhibits prostate cancer cell growth via Akt-mTOR-dependent and -independent mechanisms. Cell Death Discov. 2022;8(1).10.1038/s41420-022-00911-y.
81. Youssef M, Moussa N, W. Helmy M, Haroun M. Unraveling the therapeutic potential of GANT61/Dactolisib combination as a novel prostate cancer modality. Med Oncol. 2022;39(10).10.1007/s12032-022-01718-8.
82. Feng Y, Jiang Y, Hao F. GSK2126458 has the potential to inhibit the proliferation of pancreatic cancer uncovered by bioinformatics analysis and pharmacological experiments. J Transl Med. 2021;19(1).10.1186/s12967-021-03050-7.
83. Wise-Draper TM, Moorthy G, Salkeni MA, et al. A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Targeted Oncol. 2017;12(3):323-332.10.1007/s11523-017-0482-9.
84. Shang X, Na X, Wang L, Yang Z, Ren P. Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells. Evid-Based Complement Altern Med. 2022;2022.10.1155/2022/8110796.
85. Prat A, Brase JC, Cheng Y, et al. Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2. Oncologist. 2019;24(7):893-900.10.1634/theoncologist.2018-0407.
86. Layman RM, Han HS, Rugo HS, et al. Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study. Lancet Oncol. 2024;25(4):474-487.10.1016/S1470-2045(24)00034-2.
87. Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer. Drugs. 2020;80(16):1685-1697.10.1007/s40265-020-01394-w.
88. Dunn E, Chitcholtan K, Sykes P, Garrill A. The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models. Cancers. 2022;14(2).10.3390/cancers14020395.
89. Liu T, Sun Q, Li Q, et al. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther. 2015;14(2):429-439.10.1158/1535-7163.MCT-14-0548.
90. Valdez BC, Yuan B, Murray D, Nieto Y, Popat U, Andersson BS. Enhanced cytotoxicity of bisantrene when combined with venetoclax, panobinostat, decitabine and olaparib in acute myeloid leukemia cells. Leuk Lymphoma. 2022;63(7):1634-1644.10.1080/10428194.2022.2042689.
91. Philip CA, Laskov I, Beauchamp MC, et al. Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer. 2017;17(1).10.1186/s12885-017-3639-0.
92. Langdon SP, Kay C, Um IH, et al. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci Rep. 2019;9(1).10.1038/s41598-019-55096-9.
93. Wu YY, Wu HC, Wu JE, et al. 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. 2019;38(1).10.1186/s13046-019-1282-0.
94. Wang R, Li A, Liu J, et al. BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells. J Chemother. 2023;35(2):95-103.10.1080/1120009X.2022.2045826.
95. Wainberg ZA, Alsina M, Soares HP, et al. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Targeted Oncol. 2017;12(6):775-785.10.1007/s11523-017-0530-5.
96. Grilley-Olson JE, Bedard PL, Fasolo A, et al. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Invest New Drugs. 2016;34(6):740-749.10.1007/s10637-016-0377-0.
97. Leiphrakpam PD, Are C. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. Int J Mol Sci. 2024;25(6).10.3390/ijms25063178.
98. Zhang S, Zhu X, Gao L, et al. Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors. Journal of Clinical Oncology. 06/01 2024;42:e14627-e14627.10.1200/JCO.2024.42.16_suppl.e14627.
99. Guo Y, Xue L, Tang W, et al. 874P Preliminary outcomes from a phase Ib/II study of WX390 combined with toripalimab in patients with recurrent or metastatic head and neck squamous cell carcinoma. Annals of Oncology. 2024;35:S626.10.1016/j.annonc.2024.08.935.
100. Desravines N, Tran C, Wethington S, Williams-Brown MY. Contemporary Review of Adenocarcinoma of the Cervix. Curr Treat Options Oncol. 2024;25(12):1538-1549.10.1007/s11864-024-01254-9.
101. Zheng K, Jin G, Cao R, et al. Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma. Cancer Chemother Pharmacol. 2025;95(1).10.1007/s00280-024-04748-3.
102. Hossain MT, Hossain MA. Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes. Eur J Pharmacol. 2025;996.10.1016/j.ejphar.2025.177432.
103. Gunder LC, Moyer TH, Johnson HR, et al. Anal Cancer Prevention Through the Topical Use of Single or Dual PI3K/mTOR Inhibitors. J Surg Res. 2023;282:137-146.10.1016/j.jss.2022.09.025.
104. Janku F, Choong GM, Opyrchal M, et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers (Basel). Mar 13 2024;16(6).10.3390/cancers16061137.
105. Mardanshahi A, Gharibkandi NA, Vaseghi S, Abedi SM, Molavipordanjani S. The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines. Mol Biol Rep. 2021;48(8).10.1007/s11033-021-06607-3.
106. Wallin JJ, Edgar KA, Guan J, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011;10(12):2426-2436.10.1158/1535-7163.MCT-11-0446.
107. Mortazavi M, Moosavi F, Martini M, Giovannetti E, Firuzi O. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer. Crit Rev Oncol Hematol. 2022;176.10.1016/j.critrevonc.2022.103749.
Article Sidebar
Published
Mar 12, 2026
Article Details
How to Cite
1.
Dual inhibition of PI3K and mTOR in cancer therapy: Mechanisms, clinical potential, and future perspectives. Pharm Pract (Granada) [Internet]. 2026 Mar. 12 [cited 2026 Mar. 26];24(1):1-13. Available from: https://pharmacypractice.org/index.php/pp/article/view/3337
Section
Review
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
1.
Dual inhibition of PI3K and mTOR in cancer therapy: Mechanisms, clinical potential, and future perspectives. Pharm Pract (Granada) [Internet]. 2026 Mar. 12 [cited 2026 Mar. 26];24(1):1-13. Available from: https://pharmacypractice.org/index.php/pp/article/view/3337