71
Views
0
CrossRef citations to date
0
Altmetric
Review

Strategies and techniques for preclinical therapeutic targeting of PI3K in oncology: where do we stand in 2024?

, &
Pages 221-232 | Received 14 Sep 2023, Accepted 06 Apr 2024, Published online: 21 May 2024

References

  • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006 Aug;7(8):606–619. PubMed PMID: 16847462; eng.
  • Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019 Feb 19;18(1):26.
  • Fruman DA, Chiu H, Hopkins BD, et al. The PI3K pathway in human disease. Cell. 2017 Aug 10;170(4):605–635.
  • Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol. 2012;13(3):195–203. doi: 10.1038/nrm3290.
  • Castel P, Toska E, Engelman JA, et al. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer. 2021 Jun. 2(6):587–597. doi: 10.1038/s43018-021-00218-4. PubMed PMID: 35118422; PubMed Central PMCID: PMCPMC8809509. eng
  • Vanhaesebroeck B, Perry MWD, Brown JR, et al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021 Oct. 20(10):741–769. doi: 10.1038/s41573-021-00209-1. PubMed PMID: 34127844; PubMed Central PMCID: PMCPMC9297732. eng
  • Kriplani N, Hermida MA, Brown ER, et al. Class I PI 3-kinases: function and evolution. Adv Biol Regul. 2015 Sep;59:53–64.
  • Posor Y, Eichhorn-Gruenig M, Puchkov D, et al. Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature. 2013 Jul 11;499(7457):233–237.
  • Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol. 2022 Oct;85:69–94. doi: 10.1016/j.semcancer.2021.06.019. PubMed PMID: 34175443; eng.
  • Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, NY). 2005 Feb 18;307(5712):1098–1101.
  • Vasan N, Cantley LC. At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy. Nat Rev Clin Oncol. 2022 Jul;19(7):471–485. PubMed PMID: 35484287; eng.
  • Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug. 8(8):627–644. doi: 10.1038/nrd2926. PubMed PMID: 19644473; PubMed Central PMCID: PMCPMC3142564. eng
  • Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014 Feb;13(2):140–156. PubMed PMID: 24481312; PubMed Central PMCID: PMCPMC3994981. eng.
  • Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol Biosyst. 2015 Jul;11(7):1946–1954. PubMed PMID: 25924008; eng.
  • Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009 Aug;9(8):550–562. PubMed PMID: 19629070; eng.
  • Papa A, Pandolfi PP. The PTEN⁻PI3K axis in cancer. Biomolecules. 2019 Apr 17;9(4):153. doi: 10.3390/biom9040153. PubMed PMID: 30999672; PubMed Central PMCID: PMCPMC6523724. eng.
  • Langdon CG. Nuclear PTEN’s functions in suppressing tumorigenesis: implications for rare cancers. Biomolecules. 2023 Jan 30;13(2). doi: 10.3390/biom13020259. PubMed PMID: 36830628; PubMed Central PMCID: PMCPMC9953540. eng.
  • Haddadi N, Lin Y, Travis G, et al. PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling,’ new targets for cancer therapy. Mol Cancer. 2018 Feb 19;17(1):37.
  • Muto J, Imai T, Ogawa D, et al. RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways. PLOS ONE. 2012;7(3):e33431.
  • Wang S, Li N, Yousefi M, et al. Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat Commun. 2015 Mar 16;6(1):6517.
  • Sellars E, Gabra M, Salmena L. The complex landscape of PTEN mRNA regulation. Cold Spring Harb Perspect Med. 2020 Jun 1;10(6):a036236. doi: 10.1101/cshperspect.a036236. PubMed PMID: 31871240; PubMed Central PMCID: PMCPMC7263096. eng.
  • Gimm O, Perren A, Weng LP, et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol. 2000 May. 156(5):1693–1700. doi: 10.1016/s0002-9440(10)65040-7. PubMed PMID: 10793080; PubMed Central PMCID: PMCPMC1876937. eng
  • Hopkins BD, Hodakoski C, Barrows D, et al. PTEN function: the long and the short of it. Trends Biochem Sci. 2014 Apr. 39(4):183–190. doi: 10.1016/j.tibs.2014.02.006. PubMed PMID: 24656806; PubMed Central PMCID: PMCPMC4043120. eng
  • Tanaka M, Grossman HB. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther. 2003 Sep;10(19):1636–1642. PubMed PMID: 12923562; eng.
  • Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: biological and therapeutic significance. Semin Cancer Biol. 2019 Dec;59:147–160. doi: 10.1016/j.semcancer.2019.05.012. PubMed PMID: 31128298; eng.
  • Liang S, Yang N, Pan Y, et al. Expression of activated PIK3CA in ovarian surface epithelium results in hyperplasia but not tumor formation. PLOS ONE. 2009;4(1):e4295.
  • Wang W, Lu Z, Wang M, et al. The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma. Front Immunol. 2022;13:998236. PubMed PMID: 36110851; PubMed Central PMCID: PMCPMC9468372. eng
  • Jee J, Lebow ES, Yeh R, et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat Med. 2022 Nov. 28(11):2353–2363. doi: 10.1038/s41591-022-02047-z. PubMed PMID: 36357680; PubMed Central PMCID: PMCPMC10338177. eng
  • Dbouk HA, Khalil BD, Wu H, et al. Characterization of a tumor-associated activating mutation of the p110β PI 3-kinase. PLOS ONE. 2013;8(5):e63833.
  • Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015 Jan;15(1):7–24. PubMed PMID: 25533673; PubMed Central PMCID: PMCPMC4384662. eng.
  • Tsai PJ, Lai YH, Manne RK, et al. Akt: a key transducer in cancer. J Biomed Sci. 2022 Oct 1;29(1):76.
  • Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007 Jul 26;448(7152):439–444.
  • Tao T, Shi H, Wang M, et al. Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors. J Exp Med. 2020 Oct 5 217(10). doi: 10.1084/jem.20191871. PubMed PMID: 32728700; PubMed Central PMCID: PMCPMC7537400 grants from Rally Foundation for Childhood Cancer Research and the Open Hands Overflowing Hearts during the conduct of the study. H. Shi reported grants from Alex’s Lemonade Stand Foundation during the conduct of the study. A.T. Look reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported. eng.
  • Revathidevi S, Munirajan AK. Akt in cancer: mediator and more. Semin Cancer Biol. 2019 Dec;59:80–91. doi: 10.1016/j.semcancer.2019.06.002. PubMed PMID: 31173856; eng.
  • Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995 Aug 22;64(4):280–285.
  • Mundi PS, Sachdev J, McCourt C, et al. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016 Oct. 82(4):943–956. doi: 10.1111/bcp.13021. PubMed PMID: 27232857; PubMed Central PMCID: PMCPMC5137819. eng
  • Dummler B, Tschopp O, Hynx D, et al. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol. 2006 Nov. 26(21):8042–8051. doi: 10.1128/mcb.00722-06. PubMed PMID: 16923958; PubMed Central PMCID: PMCPMC1636753. eng
  • Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2017 May 17;9(5):52. doi: 10.3390/cancers9050052. PubMed PMID: 28513565; PubMed Central PMCID: PMCPMC5447962. eng.
  • Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012 Mar 16;148(6):1172–1187. doi: 10.1016/j.cell.2012.02.005. PubMed PMID: 22424228; PubMed Central PMCID: PMCPMC3308137. eng.
  • Sun Y, Liu W, Zhao Q, et al. Down-regulating the expression of miRNA-21 inhibits the glucose metabolism of A549/DDP cells and promotes cell death through the PI3K/AKT/mTOR/HIF-1α pathway. Front Oncol. 2021;11:653596. PubMed PMID: 34046349; PubMed Central PMCID: PMCPMC8144645. eng
  • Akbarzadeh M, Mihanfar A, Akbarzadeh S, et al. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci. 2021 Nov 15;285:119984.
  • Huang J, Chen L, Wu J, et al. Targeting the PI3K/AKT/mTOR signaling pathway in the treatment of human diseases: current status, trends, and solutions. J Med Chem. 2022 Dec 22;65(24):16033–16061.
  • Shouse G, Danilova OV, Danilov AV. Current status of phosphoinotiside-3 kinase inhibitors in blood cancers. Curr Opin Oncol. 2022 Sep 1;34(5):540–545. doi: 10.1097/cco.0000000000000871. PubMed PMID: 35855508; eng.
  • Banerjee T, Kim MS, Haslam A, et al. Clinical trials portfolio and regulatory history of idelalisib in indolent non-hodgkin lymphoma: a systematic review and meta-analysis. JAMA Internal Medicine. 2023 May 1;183(5):435–441.
  • Wang J, Zhou H, Mu M, et al. Efficacy and safety of copanlisib in relapsed/refractory B-cell non-Hodgkin lymphoma: a meta-analysis of prospective clinical trials. Front Immunol. 2022;13:1034253. PubMed PMID: 36439091; PubMed Central PMCID: PMCPMC9691663. eng
  • Paul J, Soujon M, Wengner AM, et al. Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell. 2017 Jan 9;31(1):64–78.
  • Göckeritz E, Kerwien S, Baumann M, et al. Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells. Int J Cancer. 2015 Nov 1;137(9):2234–2242.
  • Ladygina N, Gottipati S, Ngo K, et al. PI3Kγ kinase activity is required for optimal T-cell activation and differentiation. Eur J Immunol. 2013 Dec. 43(12):3183–3196. doi: 10.1002/eji.201343812. PubMed PMID: 24030559; PubMed Central PMCID: PMCPMC4209804. eng
  • Wang Z, Zhou H, Xu J, et al. Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: a systematic review and meta-analysis of prospective clinical trials. Front Immunol. 2022;13:1070660. PubMed PMID: 36685572; PubMed Central PMCID: PMCPMC9845779. eng
  • Maharaj K, Powers JJ, Achille A, et al. The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020 Jul 14;4(13):3072–3084.
  • Royer B, Kaderbhaï CG, Schmitt A. Pharmacokinetics and pharmacodynamic of alpelisib. Clin Pharmacokinet. 2023 Jan;62(1):45–53. PubMed PMID: 36633813; eng.
  • Ye Y, Huang Z, Zhang M, et al. Synergistic therapeutic potential of alpelisib in cancers (excluding breast cancer): preclinical and clinical evidences. Biomed Pharmacothe. 2023 Mar;159:114183.
  • Dong C, Chen Y, Li H, et al. The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer. Int J Biol Sci. 2019;15(7):1523–1532.
  • Joshi S, Liu KX, Zulcic M, et al. Macrophage Syk-PI3Kγ inhibits antitumor immunity: SRX3207, a novel dual syk-PI3K inhibitory chemotype relieves tumor immunosuppression. Mol Cancer Ther. 2020 Mar. 19(3):755–764. doi: 10.1158/1535-7163.Mct-19-0947. PubMed PMID: 31974273; PubMed Central PMCID: PMCPMC7450492. eng
  • De Henau O, Rausch M, Winkler D, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016 Nov 17;539(7629):443–447.
  • Ji M, Wang D, Lin S, et al. A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models. Acta Pharm Sin B. 2022 Feb. 12(2):774–786. doi: 10.1016/j.apsb.2021.05.019. PubMed PMID: 35256946; PubMed Central PMCID: PMCPMC8897175. eng
  • Sun P, Meng LH. Emerging roles of class I PI3K inhibitors in modulating tumor microenvironment and immunity. Acta Pharmacol Sin. 2020 Nov;41(11):1395–1402. PubMed PMID: 32939035; PubMed Central PMCID: PMCPMC7656798. eng.
  • Ali K, Soond DR, Pineiro R, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014 Jun 19;510(7505):407–411.
  • Bowers JS, Majchrzak K, Nelson MH, et al. PI3Kδ inhibition enhances the antitumor fitness of adoptively transferred CD8(+) T cells. Front Immunol. 2017;8:1221. PubMed PMID: 29033940; PubMed Central PMCID: PMCPMC5626814. eng
  • Stanciu S, Ionita-Radu F, Stefani C, et al. Targeting PI3K/AKT/mTOR signaling pathway in pancreatic cancer: from molecular to clinical aspects. Int J Mol Sci. 2022 Sep 4;23(17):10132.
  • Awasthi N, Yen PL, Schwarz MA, et al. The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J Cell Biochem. 2012 Mar. 113(3):784–791. doi: 10.1002/jcb.23405. PubMed PMID: 22020918; eng
  • Tarantelli C, Lupia A, Stathis A, et al. Is there a role for dual PI3K/mTOR inhibitors for patients affected with lymphoma? Int J Mol Sci. 2020 Feb 5;21(3):1060.
  • Wu X, Xu Y, Liang Q, et al. Recent advances in dual PI3K/mTOR inhibitors for tumour treatment. Front Pharmacol. 2022;13:875372. PubMed PMID: 35614940; PubMed Central PMCID: PMCPMC9124774. eng
  • Mahadevan D, Chiorean EG, Harris WB, et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer. 2012 Dec. 48(18):3319–3327. doi: 10.1016/j.ejca.2012.06.027. PubMed PMID: 22921184; PubMed Central PMCID: PMCPMC3826796. eng
  • Han J, Chen Y, Yang C, et al. Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor. Eur J Med Chem. 2016 Oct 21;122:684–701.
  • Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012 Jan;16(1):121–130. PubMed PMID: 22239433; eng.
  • Nitulescu GM, Margina D, Juzenas P, et al. Akt inhibitors in cancer treatment: the long journey from drug discovery to clinical use (Review). Int J Oncol. 2016 Mar. 48(3):869–885. doi: 10.3892/ijo.2015.3306. PubMed PMID: 26698230; PubMed Central PMCID: PMCPMC4750533. eng
  • Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019 Dec;59:125–132. doi: 10.1016/j.semcancer.2019.07.009. PubMed PMID: 31323288; eng.
  • Suzuki A, de la Pompa JL, Stambolic V, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998 Oct 22;8(21):1169–1178.
  • Mao B, Zhang Q, Ma L, et al. Overview of Research into mTOR Inhibitors. Molecules. 2022 Aug 19;27(16):5295.
  • Rashid MM, Lee H, Jung BH. Metabolite identification and pharmacokinetic profiling of PP242, an ATP-competitive inhibitor of mTOR using ultra high-performance liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Jan 1; 1072:244–251. doi: 10.1016/j.jchromb.2017.11.027. PubMed PMID: 29195143; eng.
  • Rodrik-Outmezguine VS, Okaniwa M, Yao Z, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9;534(7606):272–276.
  • Duncan L, Shay C, Teng Y. PI3K isoform-selective inhibitors in cancer. Adv Exp Med Biol. 2020:1255:165–173. doi: 10.1007/978-981-15-4494-1_14. PubMed PMID: 32949399; eng.
  • Sato H, Yamamoto H, Sakaguchi M, et al. Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Cancer Sci. 2018 Oct. 109(10):3183–3196. doi: 10.1111/cas.13763. PubMed PMID: 30098066; PubMed Central PMCID: PMCPMC6172047. eng
  • Solzak JP, Atale RV, Hancock BA, et al. Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple negative breast cancer. NPJ Breast Cancer. 2017;3(1):17.
  • Kim HR, Kang HN, Yun MR, et al. Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck. Br J Cancer. 2020 Dec. 123(12):1720–1729. doi: 10.1038/s41416-020-01074-2. PubMed PMID: 32963347; PubMed Central PMCID: PMCPMC7722843. eng
  • Alqahtani FY, Aleanizy FS, El Tahir E, et al. Paclitaxel. Profiles of drug substances, excipients, and related methodology. Prof Drug Subst Excipients Related Method. 2019;44:205–238. PubMed PMID: 31029218; eng
  • Tewari D, Patni P, Bishayee A, et al. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin Cancer Biol. 2022 May;80:1–17.
  • Huw LY, O’Brien C, Pandita A, et al. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer. Oncogenesis. 2013 Dec 23;2(12):e83.
  • Juric D, Castel P, Griffith M, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015 Feb 12;518(7538):240–244.
  • Elkabets M, Vora S, Juric D, et al. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med. 2013 Jul 31;5(196):196ra99.
  • Wang J, Lv X, Guo X, et al. Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells. Oncogenesis. 2021 Jan 5;10(1):8.
  • Neklesa TK, Davis RW. Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex. Proc Natl Acad Sci USA. 2008 Sep 30;105(39):15166–15171. doi: 10.1073/pnas.0807712105. PubMed PMID: 18812505; PubMed Central PMCID: PMCPMC2567509. eng.
  • Koh KX, Tan GH, Hui Low SH, et al. Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis. Oncotarget. 2017 Dec 15;8(66):110133–110144.
  • Makinoshima H, Umemura S, Suzuki A, et al. Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma. Cancer Res. 2018 May 1;78(9):2179–2190.
  • Icard P, Simula L, Fournel L, et al. The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: therapeutic implications. Drug Resist Updat. 2022 Jul;63:100852.
  • Shepherd C, Banerjee L, Cheung CW, et al. PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. Leukemia. 2013 Mar. 27(3):650–660. doi: 10.1038/leu.2012.285. PubMed PMID: 23038273; eng
  • Song L, Zhou Z, Gan Y, et al. Long noncoding RNA OIP5-AS1 causes cisplatin resistance in osteosarcoma through inducing the LPAATβ/PI3K/AKT/mTOR signaling pathway by sponging the miR-340-5p. J Cell Biochem. 2019 Jun. 120(6):9656–9666. doi: 10.1002/jcb.28244. PubMed PMID: 30548308; eng
  • Konstantinopoulos PA, Barry WT, Birrer M, et al. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019 Apr. 20(4):570–580. doi: 10.1016/s1470-2045(18)30905-7. PubMed PMID: 30880072; PubMed Central PMCID: PMCPMC7025391. eng
  • Sharma P, Abramson VG, O’Dea A, et al. Clinical and biomarker results from phase I/II study of PI3K inhibitor alpelisib plus nab-paclitaxel in HER2-negative metastatic breast cancer. Clin Cancer Res off J Am Assoc Cancer Res. 2021 Jul 15;27(14):3896–3904.
  • Rugo HS, André F, Yamashita T, et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol. 2020 Aug. 31(8):1001–1010. doi: 10.1016/j.annonc.2020.05.001. PubMed PMID: 32416251; eng
  • Esposito A, Viale G, Safety CG. Tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: a review. JAMA Oncol. 2019 Sep 1;5(9):1347–1354. doi: 10.1001/jamaoncol.2019.0034. PubMed PMID: 30920609; eng.
  • Yoon MS. Nanotechnology-based targeting of mTOR signaling in cancer. Int J Nanomedicine. 2020:15:5767–5781. doi: 10.2147/ijn.S254574. PubMed PMID: 32821100; PubMed Central PMCID: PMCPMC7418174. eng.
  • Fan Y, Marioli M, Zhang K. Analytical characterization of liposomes and other lipid nanoparticles for drug delivery. J Pharm Biomed Anal. 2021 Jan 5; 192:113642. doi: 10.1016/j.jpba.2020.113642. PubMed PMID: 33011580; eng.
  • Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520–529.
  • Vasan N, Razavi P, Johnson JL, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science (New York, NY). 2019 Nov 8;366(6466):714–723.
  • Langdon S, Hughes A, Taylor MA, et al. Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity. Oncoimmunology. 2018;7(8):e1458810.
  • Wang Y, Wang XY, Subjeck JR, et al. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br J Cancer. 2011 Feb 15;104(4):643–652.
  • Lattanzio L, Tonissi F, Monteverde M, et al. Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines. Invest New Drugs. 2015 Apr. 33(2):310–320. doi: 10.1007/s10637-015-0210-1. PubMed PMID: 25603975; eng
  • You I, Erickson EC, Donovan KA, et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem Biol. 2020 Jan 16;27(1):66–73.e7.
  • Guenette RG, Yang SW, Min J, et al. Target and tissue selectivity of PROTAC degraders. Chem Soc Rev. 2022 Jul 18;51(14):5740–5756.
  • Pei J, Wang G, Feng L, et al. Targeting lysosomal degradation pathways: new strategies and techniques for drug discovery. J Med Chem. 2021 Apr 8;64(7):3493–3507.
  • Edwards NJ, Oberti M, Thangudu RR, et al. The CPTAC data portal: a resource for cancer proteomics research. J Proteome Res. 2015 Jun 5;14(6):2707–2713.
  • Mishra R, Patel H, Alanazi S, et al. PI3K inhibitors in cancer: clinical implications and adverse effects. Int J Mol Sci. 2021 Mar 27;22(7):3464.
  • Dhimolea E, de Matos Simoes R, Kansara D, et al. An embryonic diapause-like adaptation with suppressed myc activity enables tumor treatment persistence. Cancer Cell. 2021 Feb 8;39(2):240–256.e11.
  • Wu D, Li Y, Zheng L, et al. Small molecules targeting protein-protein interactions for cancer therapy. Acta Pharm Sin B. 2023 Oct. 13(10):4060–4088. doi: 10.1016/j.apsb.2023.05.035. PubMed PMID: 37799384; PubMed Central PMCID: PMCPMC10547922. eng
  • O’Donnell JS, Massi D, Teng MWL, et al. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol. 2018 Feb;48:91–103.
  • Zheng L, Li Y, Wu D, et al. Development of covalent inhibitors: principle, design, and application in cancer. MedComm Oncol. 2023;2(4):e56.
  • Keles E, Borsari C, Sriramaratnam R, et al. Abstract 1378: a novel, highly potent PI3Kα covalent inhibitor deconvolutes class I PI3K isoforms in cancer cells. Cancer Res. 2021;81(13_Supplement):1378.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.