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Review Article | Open Access

Oncogenic activation of PIK3CA in cancers: Emerging targeted therapies in precision oncology

Yuxiang Wanga,b,1, Valery Rozena,b,c,1, Yiqing Zhaoa,b, Zhenghe Wanga,b( )
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

Phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. The PIK3CA gene, which encodes the p110α, is the most frequently mutated oncogene in cancer. Oncogenic PIK3CA mutations activate the PI3K pathway, promote tumor initiation and development, and mediate resistance to anti-tumor treatments, making the mutant p110α an excellent target for cancer therapy. PIK3CA mutations occur in two hotspot regions: one in the helical domain and the other in the kinase domain. The PIK3CA helical and kinase domain mutations exert their oncogenic function through distinct mechanisms. For example, helical domain mutations of p110α gained direct interaction with insulin receptor substrate 1 (IRS-1) to activate the downstream signaling pathways. Moreover, p85β proteins disassociate from helical domain mutant p110α, translocate into the nucleus, and stabilize enhancer of zeste homolog 1/2 (EZH1/2). Due to the fundamental role of PI3Kα in tumor initiation and development, PI3Kα-specific inhibitors, represented by FDA-approved alpelisib, have developed rapidly in recent decades. However, side effects, including on-target side effects such as hyperglycemia, restrict the maximum dose and thus clinical efficacy of alpelisib. Therefore, developing p110α mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant cancers. In this review, we briefly introduce the function of the PI3K pathway and discuss how PIK3CA mutations rewire cell signaling, metabolism, and tumor microenvironment, as well as therapeutic strategies under development to treat patients with tumors harboring a PIK3CA mutation.

Keywords

Hotspot mutationIsoform/mutant-specific inhibitorsMetabolismPIK3CATumor microenvironment

References

1

Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605-635.
Crossref Google Scholar
2

Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554.
Crossref Google Scholar
3

Markham A. Alpelisib: first global approval. Drugs. 2019;79(11):1249-1253.
Crossref Google Scholar
4

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;19(7):471-485.
Crossref Google Scholar
5

Sahlberg SH, Mortensen AC, Haglöf J, et al. Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. Int J Oncol. 2017;50(1):5-14.
Crossref Google Scholar
6

Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138.
Crossref Google Scholar
7

Karalis V, Wood D, Teaney NA, Sahin M. The role of TSC1 and TSC2 proteins in neuronal axons. Mol Psychiatr. 2024;29(4):1165-1178.
Crossref Google Scholar
8

Chandran D, Jayaraman S, Sankaran K, Veeraraghavan VP, R G. Antioxidant vitamins attenuate glyphosate-induced development of type-2 diabetes through the activation of glycogen synthase kinase-3 β and forkhead box protein O-1 in the liver of adult male rats. Cureus. 2023;15(12):e51088.
Google Scholar
9

Ebrahimnezhad M, Natami M, Bakhtiari GH, et al. FOXO1, a tiny protein with intricate interactions: promising therapeutic candidate in lung cancer. Biomed Pharmacother. 2023;169:115900.
Crossref Google Scholar
10

Reagan-Shaw S, Ahmad N. The role of forkhead-box class O (FoxO) transcription factors in cancer: a target for the management of cancer. Toxicol Appl Pharmacol. 2007;224(3):360-368.
Crossref Google Scholar
11

Pozo FM, Hunter T, Zhang Y. The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K. Acta Mater Med. 2022;1(2):193-196.
Google Scholar
12

Rathinaswamy MK, Burke JE. Class I phosphoinositide 3-kinase (PI3K) regulatory subunits and their roles in signaling and disease. Adv Biol Regul. 2020;75:100657.
Crossref Google Scholar
13

Rodriguez-Viciana P, Warne PH, Dhand R, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994;370(6490):527-532.
Crossref Google Scholar
14

Hager M, Chang P, Lee M, et al. Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice. Geroscience. 2024;46(2):2653-2670.
Google Scholar
15

Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20(10):741-769.
Crossref Google Scholar
16

Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495-501.
Crossref Google Scholar
17

Huang CH, Mandelker D, Schmidt-Kittler O, et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007;318(5857):1744-1748.
Crossref Google Scholar
18

Hao Y, Zhao S, Wang Z. Targeting the protein-protein interaction between IRS1 and mutant p110α for cancer therapy. Toxicol Pathol. 2014;42(1):140-147.
Crossref Google Scholar
19

Zhang M, Jang H, Nussinov R. PI3K driver mutations: a biophysical membrane-centric perspective. Cancer Res. 2021;81(2):237-247.
Crossref Google Scholar
20

Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A. 2008;105(7):2652-2657.
Crossref Google Scholar
21

Hao Y, Wang C, Cao B, et al. Gain of interaction with IRS1 by p110α-helical domain mutants is crucial for their oncogenic functions. Cancer Cell. 2013;23(5):583-593.
Crossref Google Scholar
22

Hu X, He Y, Wu L, Hao Y, Wang Z, Zheng W. Novel all-hydrocarbon stapled p110α[E545K]peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction. Bioorg Med Chem Lett. 2017;27(24):5446-5449.
Crossref Google Scholar
23

Hao Y, He B, Wu L, et al. Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer. Nat Commun. 2022;13(1):1974.
Crossref Google Scholar
24

Xing H, Gao M, Wang Y, et al. Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma. Clin Transl Med. 2022;12(5):e835.
Crossref Google Scholar
25

Mandelker D, Gabelli SB, Schmidt-Kittler O, et al. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009;106(40):16996-17001.
Crossref Google Scholar
26

Hart JR, Liu X, Pan C, et al. Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα. Proc Natl Acad Sci USA. 2022;119(38):e2210769119.
Crossref Google Scholar
27

Liu X, Zhou Q, Hart JR, et al. Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα. Proc Natl Acad Sci USA. 2022;119(46):e2215621119.
Crossref Google Scholar
28

Varkaris A, Pazolli E, Gunaydin H, et al. Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Kα inhibitor that decouples antitumor activity from hyperinsulinemia. Cancer Discov. 2024;14(2):240-257.
Crossref Google Scholar
29

Leontiadou H, Galdadas I, Athanasiou C, Cournia Z. Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations. Sci Rep. 2018;8(1):15544.
Crossref Google Scholar
30

Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619-634.
Crossref Google Scholar
31

Hao Y, Samuels Y, Li Q, et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun. 2016;7:11971.
Crossref Google Scholar
32

Zhao Y, Zhao X, Chen V, et al. Colorectal cancers utilize glutamine as an anaplerotic substrate of the TCA cycle in vivo. Sci Rep. 2019;9(1):19180.
Crossref Google Scholar
33

Zhao Y, Feng X, Chen Y, et al. 5-fluorouracil enhances the antitumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers. Cancer Res. 2020;80(21):4815-4827.
Crossref Google Scholar
34

Li Y, Wu S, Zhao Y, et al. Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer. J Clin Invest. 2024;134(5):e175031.
Crossref Google Scholar
35

Burn GL, Foti A, Marsman G, Patel DF, Zychlinsky A. The neutrophil. Immunity. 2021;54(7):1377-1391.
Crossref Google Scholar
36

Calera MR, Martinez C, Liu H, Jack AK, Birnbaum MJ, Pilch PF. Insulin increases the association of Akt-2 with Glut4-containing vesicles. J Biol Chem. 1998;273(13):7201-7204.
Crossref Google Scholar
37

Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74-88.
Crossref Google Scholar
38

Waldhart AN, Dykstra H, Peck AS, et al. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Rep. 2017;19(10):2005-2013.
Crossref Google Scholar
39

Nissler K, Petermann H, Wenz I, Brox D. Fructose 2, 6-bisphosphate metabolism in Ehrlich ascites tumour cells. J Cancer Res Clin Oncol. 1995;121(12):739-745.
Crossref Google Scholar
40

Jin MZ, Jin WL. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Targeted Ther. 2020;5(1):166.
Crossref Google Scholar
41

Tang H, Qiao J, Fu YX. Immunotherapy and tumor microenvironment. Cancer Lett. 2016;370(1):85-90.
Crossref Google Scholar
42

Sun P, Meng LH. Emerging roles of class I PI3K inhibitors in modulating tumor microenvironment and immunity. Acta Pharmacol Sin. 2020;41(11):1395-1402.
Crossref Google Scholar
43

Aydin E, Faehling S, Saleh M, Llaó Cid L, Seiffert M, Roessner PM. Phosphoinositide 3-kinase signaling in the tumor microenvironment: what do we need to consider when treating chronic lymphocytic leukemia with PI3K inhibitors? Front Immunol. 2021;11:595818.
Crossref Google Scholar
44

Koyasu S. The role of PI3K in immune cells. Nat Immunol. 2003;4(4):313-319.
Crossref Google Scholar
45

Li Y, Liu Z, Zhao Y, et al. PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain. Genes Dis. 2022;10(4):1702-1713.
Crossref Google Scholar
46

Amable G, Martínez-León E, Picco ME, et al. Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol. 2019;112:88-94.
Crossref Google Scholar
47

Du L, Lee JH, Jiang H, et al. β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion. J Exp Med. 2020;217(11):e20191115.
Crossref Google Scholar
48

Li CW, Lim SO, Xia W, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632.
Crossref Google Scholar
49

Dong Y, Richards JA, Gupta R, et al. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene. 2014;33(38):4632-4642.
Crossref Google Scholar
50

Su WY, Tian LY, Guo LP, Huang LQ, Gao WY. PI3K signaling-regulated metabolic reprogramming: from mechanism to application. Biochim Biophys Acta Rev Cancer. 2023;1878(5):188952.
Crossref Google Scholar
51

Shang S, Wang MZ, Xing Z, He N, Li S. Lactate regulators contribute to tumor microenvironment and predict prognosis in lung adenocarcinoma. Front Immunol. 2022;13:1024925.
Crossref Google Scholar
52

Haas R, Smith J, Rocher-Ros V, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015;13(7):e1002202.
Crossref Google Scholar
53

Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.
Google Scholar
54

Zhang Y, Huang H, Coleman M, et al. VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment. JCI Insight. 2021;6(23):e150735.
Crossref Google Scholar
55

Horikawa N, Abiko K, Matsumura N, et al. Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res. 2017;23(2):587-599.
Crossref Google Scholar
56

Freire Valls A, Knipper K, Giannakouri E, et al. VEGFR1+ metastasis-associated macrophages ccontribute to metastatic angiogenesis and influence colorectal cancer patient outcome. Clin Cancer Res. 2019;25(18):5674-5685.
Crossref Google Scholar
57

Zou Y, Chen Q, Ye Z, Li X, Ju R. VEGFR1 signaling regulates IL-4-mediated arginase 1 expression in macrophages. Curr Mol Med. 2017;17(4):304-311.
Google Scholar
58

Wada J, Suzuki H, Fuchino R, et al. The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res. 2009;29(3):881-888.
Google Scholar
59

Ziogas AC, Gavalas NG, Tsiatas M, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int J Cancer. 2012;130(4):857-864.
Crossref Google Scholar
60

Gavalas NG, Tsiatas M, Tsitsilonis O, et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br J Cancer. 2012;107(11):1869-1875.
Crossref Google Scholar
61

Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73(2):539-549.
Crossref Google Scholar
62

Bai WK, Zhang W, Hu B. Vascular endothelial growth factor suppresses dendritic cells function of human prostate cancer. OncoTargets Ther. 2018;11:1267-1274.
Crossref Google Scholar
63

Boissel N, Rousselot P, Raffoux E, et al. Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. Leukemia. 2004;18(10):1656-1661.
Crossref Google Scholar
64

André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217.
Crossref Google Scholar
65

Martínez-Sáez O, Chic N, Pascual T, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22(1):45.
Crossref Google Scholar
66

Fillbrunn M, Signorovitch J, André F, et al. PIK3CA mutation status, progression and survival in advanced HR+/HER2− breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002.
Crossref Google Scholar
67

Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2− metastatic breast cancer. Int J Breast Cancer. 2020;2020:3759179.
Google Scholar
68

Savas P, Lo LL, Luen SJ, et al. Alpelisib monotherapy for PI3K-altered, pretreated advanced breast cancer: a phase II study. Cancer Discov. 2022;12(9):2058-2073.
Crossref Google Scholar
69

Hester A, Henze F, Travi C, Harbeck N, Wuerstlein R. First experiences with alpelisib in clinical routine: case reports from a German breast center. Breast Care. 2021;16(2):129-134.
Crossref Google Scholar
70

Alaklabi S, Roy AM, Attwood K, et al. Real world outcomes with alpelisib in metastatic hormone receptor-positive breast cancer patients: a single institution experience. Front Oncol. 2022;12:1012391.
Crossref Google Scholar
71
Jhaveri KL, Im S-A, Saura C, et al. Phase III Study of Inavolisib or Placebo in Combination with Palbociclib and Fulvestrant in Patients with PIK3CA-mutant, Hormone Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer: INAVO120 Primary Analysis. San Antonio Breast Cancer Symposium; 2023. Abstract GS03-13.
72

Song KW, Edgar KA, Hanan EJ, et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (inavolisib) efficacy. Cancer Discov. 2022;12(1):204-219.
Crossref Google Scholar
73

Starks DC, Rojas-Espaillat L, Meissner T, Williams CB. Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors. Gynecol Oncol. 2022;166(3):403-409.
Crossref Google Scholar
74

Choueiri TK, Porta C, Suárez C, et al. Randomized phase II trial of sapanisertib ± TAK-117 vs. everolimus in patients with advanced renal cell carcinoma after VEGF-targeted therapy. Oncol. 2022;27(12):1048-1057.
Crossref Google Scholar
75

Juric D, de Bono JS, LoRusso PM, et al. A first-in-human, phase I, dose-escalation study of TAK-117, a selective PI3Kα isoform inhibitor, in patients with advanced solid malignancies. Clin Cancer Res. 2017;23(17):5015-5023.
Google Scholar
76

Wei XL, Liu FR, Liu JH, et al. First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors. Nat Commun. 2022;13(1):7012.
Google Scholar
77

Xiang HY, Wang X, Chen YH, et al. Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2, 1-f][1, 2, 4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors. Eur J Med Chem. 2021;209:112913.
Google Scholar
78

André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940.
Crossref Google Scholar
79

Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22(4):489-498.
Google Scholar
80

Varkaris A, de la Cruz FF, Martin EE, et al. Allosteric PI3Kα inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations. Cancer Discov. 2024;14(2):227-239.
Crossref Google Scholar
81

Kearney AL, Vasan N. A new wave of PI3Kα inhibitors. Cancer Discov. 2023;13(11):2313-2315.
Crossref Google Scholar
82

Buckbinder L, St Jean Jr DJ, Tieu T, et al. STX-478, a mutant-selective, allosteric PI3Kα inhibitor spares metabolic dysfunction and improves therapeutic response in PI3Kα-mutant xenografts. Cancer Discov. 2023;13(11):2432-2447.
Crossref Google Scholar
83

Puca L, Dowless MS, Perez-Ferreiro CM, et al. LOXO-783: a potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models. Cancer Res. 2023;83(5_suppl ment):P4-08-02.
Google Scholar
84

Klippel A, Wang R, Puca L, et al. Preclinical characterization of LOX-22783, a highly potent, mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor. Mol Cancer Therapeut. 2021;20(12_Supplement):P142.
Crossref Google Scholar
85

Juric D, Jhaveri K, Beeram M, et al. A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress). Cancer Res. 2023;83(5_suppl ment):OT3-08-01.
Google Scholar
86

Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252-260.
Crossref Google Scholar
Genes & Diseases
Volume 12 Issue 2,
March 2025
Article number: 101430
DOI: 10.1016/j.gendis.2024.101430
Cite this article:
Wang Y, Rozen V, Zhao Y, et al. Oncogenic activation of PIK3CA in cancers: Emerging targeted therapies in precision oncology. Genes & Diseases, 2025, 12(2): 101430. https://doi.org/10.1016/j.gendis.2024.101430

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Received: 03 June 2024
Revised: 04 August 2024
Accepted: 25 August 2024
Published: 10 September 2024
© 2024 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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