AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
PDF (2.2 MB)
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Review Article | Open Access

Synthetic lethal approaches to target cancers with loss of PTEN function

Ayse Ertaya( )Rob M. Ewinga,bYihua Wanga,b,( )
Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumor phenotype and tumorigenesis. Identifying targeted therapies for inactive tumor suppressor genes such as PTEN has been challenging as it is difficult to restore the tumor suppressor functions. Therefore, focusing on the downstream signaling pathways to discover a targeted therapy for inactive tumor suppressor genes has highlighted the importance of synthetic lethality studies. This review focused on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.

References

1

Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13(5):283–296.

2

Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15(4):356–362.

3

Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57(11):2124–2129.

4

Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–1947.

5

Kechagioglou P, Papi RM, Provatopoulou X, et al. Tumor suppressor PTEN in breast cancer: heterozygosity, mutations and protein expression. Anticancer Res. 2014;34(3):1387–1400.

6

Di Cristofano A, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998;19(4):348–355.

7

Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95(1):29–39.

8

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;8(21):1169–1178.

9

Podsypanina K, Ellenson LH, Nemes A, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96(4):1563–1568.

10

Sun H, Lesche R, Li DM, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3, 4, 5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1999;96(11):6199–6204.

11

Liliental J, Moon SY, Lesche R, et al. Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases. Curr Biol. 2000;10(7):401–404.

12

Stambolic V, Tsao MS, MacPherson D, et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res. 2000;60(13):3605–3611.

13

Backman SA, Stambolic V, Suzuki A, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29(4):396–403.

14

Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;11(4):289–301.

15

Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol. 1998;143(5):1375–1383.

16

Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A. 1998;95(26):15406–15411.

17

Puc J, Parsons R. PTEN loss inhibits CHK1 to cause double stranded-DNA breaks in cells. Cell Cycle. 2005;4(7):927–929.

18

Lee JO, Yang H, Georgescu MM, et al. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999;99(3):323–334.

19

Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999;96(8):4240–4245.

20

Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008;27(41):5443–5453.

21

Campbell RB, Liu F, Ross AH. Allosteric activation of PTEN phosphatase by phosphatidylinositol 4, 5-bisphosphate. J Biol Chem. 2003;278(36):33617–33620.

22

Walker SM, Leslie NR, Perera NM, et al. The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem J. 2004;379(Pt 2):301–307.

23

Georgescu MM, Kirsch KH, Akagi T, et al. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci U S A. 1999;96(18):10182–10187.

24

Fanning AS, Anderson JM. Protein modules as organizers of membrane structure. Curr Opin Cell Biol. 1999;11(4):432–439.

25

Das S, Dixon JE, Cho W. Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci U S A. 2003;100(13):7491–7496.

26

Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157–170.

27

Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998;95(23):13513–13518.

28

Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997;94(17):9052–9057.

29

Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol. 2003;13(9):478–483.

30

Leslie NR, Downes CP. PTEN function: how normal cells control it and tumour cells lose it. Biochem J. 2004;382(Pt 1):1–11.

31

Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22(14):2954–2963.

32

Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem. 1998;273(22):13375–13378.

33

Klippel A, Kavanaugh WM, Pot D, et al. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol. 1997;17(1):338–344.

34

Ziemba BP, Pilling C, Calleja V, et al. The PH domain of phosphoinositide-dependent kinase-1 exhibits a novel, phospho-regulated monomer-dimer equilibrium with important implications for kinase domain activation: single-molecule and ensemble studies. Biochemistry. 2013;52(28):4820–4829.

35

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–1274.

36

Nakamura N, Ramaswamy S, Vazquez F, et al. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol. 2000;20(23):8969–8982.

37

Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231–241.

38

Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001;98(20):11598–11603.

39

Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–657.

40

Vander Haar E, Lee SI, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007;9(3):316–323.

41

Sekulić A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60(13):3504–3513.

42

Dodd KM, Yang J, Shen MH, et al. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene. 2015;34(17):2239–2250.

43

Luo JL, Tan W, Ricono JM, et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature. 2007;446(7136):690–694.

44

Sheng S, Qiao M, Pardee AB. Metastasis and AKT activation. J Cell Physiol. 2009;218(3):451–454.

45

Diehl JA, Cheng M, Roussel MF, et al. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12(22):3499–3511.

46

Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009;4:127–150.

47

Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008;133(3):403–414.

48

Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19(9):547–562.

49

Agrawal S, Pilarski R, Eng C. Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN. Hum Mol Genet. 2005;14(16):2459–2468.

50

Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999;8(8):1461–1472.

51

Zhou X, Hampel H, Thiele H, et al. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet. 2001;358(9277):210–211.

52

Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7(3):507–515.

53

Molinari F, Frattini M. Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol. 2013;3:326.

54

Tan MH, Mester J, Peterson C, et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88(1):42–56.

55

Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16(1):64–67.

56

Chow LML, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Lett. 2006;241(2):184–196.

57

Bazzichetto C, Conciatori F, Pallocca M, et al. PTEN as a prognostic/predictive biomarker in cancer: an unfulfilled promise? Cancers. 2019;11(4):435.

58

Trotman LC, Wang X, Alimonti A, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007;128:141–156.

59

Mirmohammadsadegh A, Marini A, Nambiar S, et al. Epigenetic silencing of the PTEN gene in melanoma. Cancer Res. 2006;66(13):6546–6552.

60

García JM, Silva J, Peña C, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004;41(2):117–124.

61

Lu J, Jeong HW, Kong N, et al. Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS One. 2009;4(5):e5577.

62

Zhang HY, Liang F, Jia ZL, et al. PTEN mutation, methylation and expression in breast cancer patients. Oncol Lett. 2013;6:161–168.

63

Stambolic V, MacPherson D, Sas D, et al. Regulation of PTEN transcription by p53. Mol Cell. 2001;8(2):317–325.

64

Moorehead RA, Hojilla CV, De Belle I, et al. Insulin-like growth factor-Ⅱ regulates PTEN expression in the mammary gland. J Biol Chem. 2003;278(50):50422–50427.

65

Patel L, Pass I, Coxon P, et al. Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN. Curr Biol. 2001;11(10):764–768.

66

Zhang W, Wu N, Li Z, et al. PPARγ activator rosiglitazone inhibits cell migration via upregulation of PTEN in human hepatocarcinoma cell line BEL-7404. Cancer Biol Ther. 2006;5(8):1008–1014.

67

Whelan JT, Forbes SL, Bertrand FE. CBF-1 (RBP-J kappa) binds to the PTEN promoter and regulates PTEN gene expression. Cell Cycle. 2007;6(1):80–84.

68

Xia D, Srinivas H, Ahn YH, et al. Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NFκB-dependent pathway. J Biol Chem. 2007;282(6):3507–3519.

69

Mahimainathan L, Das F, Venkatesan B, et al. Mesangial cell hypertrophy by high glucose is mediated by downregulation of the tumor suppressor PTEN. Diabetes. 2006;55(7):2115–2125.

70

Chow JYC, Quach KT, Cabrera BL, et al. RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells. Carcinogenesis. 2007;28(11):2321–2327.

71

Hettinger K, Vikhanskaya F, Poh MK, et al. c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ. 2007;14(2):218–229.

72

Lee JY, Kang MB, Jang SH, et al. Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. Oncogene. 2009;28(6):824–831.

73

Song LB, Li J, Liao WT, et al. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119(12):3626–3636.

74

Escrivà M, Peiró S, Herranz N, et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol. 2008;28(5):1528–1540.

75

Tay Y, Song SJ, Pandolfi PP. The lilliputians and the giant: an emerging oncogenic microRNA network that suppresses the PTEN tumor suppressor in vivo. MicroRNA. 2013;2(2):127–136.

76

Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–658.

77

Zhang JG, Wang JJ, Zhao F, et al. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411(11-12):846–852.

78

Poliseno L, Salmena L, Riccardi L, et al. Identification of the miR-106b∼25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal. 2010;3(117):ra29.

79

Ciuffreda L, Di Sanza C, Incani UC, et al. The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms. J Mol Med. 2012;90(6):667–679.

80

Mu P, Han YC, Betel D, et al. Genetic dissection of the miR-17∼92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev. 2009;23(24):2806–2811.

81

Poliseno L, Salmena L, Zhang J, et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–1038.

82

Miller SJ, Lou DY, Seldin DC, et al. Direct identification of PTEN phosphorylation sites. FEBS Lett. 2002;528(1-3):145–153.

83

Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 2001;276(2):993–998.

84

Vazquez F, Grossman SR, Takahashi Y, et al. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem. 2001;276(52):48627–48630.

85

Mehenni H, Lin-Marq N, Buchet-Poyau K, et al. LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum Mol Genet. 2005;14(15):2209–2219.

86

Al-Khouri AM, Ma Y, Togo SH, et al. Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta. J Biol Chem. 2005;280(42):35195–35202.

87

Yim EK, Peng G, Dai H, et al. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell. 2009;15(4):304–314.

88

Li Z, Dong X, Wang Z, et al. Regulation of PTEN by Rho small GTPases. Nat Cell Biol. 2005;7(4):399–404.

89

Wang X, Trotman LC, Koppie T, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007;128(1):129–139.

90

Amodio N, Scrima M, Palaia L, et al. Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. Am J Pathol. 2010;177(5):2622–2634.

91

Okumura K, Mendoza M, Bachoo RM, et al. PCAF modulates PTEN activity. J Biol Chem. 2006;281(36):26562–26568.

92

Lee SR, Yang KS, Kwon J, et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002;277(23):20336–20342.

93

Takahashi Y, Morales FC, Kreimann EL, et al. PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling. EMBO J. 2006;25(4):910–920.

94

Wu X, Hepner K, Castelino-Prabhu S, et al. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci U S A. 2000;97(8):4233–4238.

95

Lima-Fernandes E, Enslen H, Camand E, et al. Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins. EMBO J. 2011;30(13):2557–2568.

96

van Diepen MT, Parsons M, Downes CP, et al. MyosinV controls PTEN function and neuronal cell size. Nat Cell Biol. 2009;11(10):1191–1196.

97

Okumura K, Zhao M, Depinho RA, et al. Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor. Proc Natl Acad Sci U S A. 2005;102(8):2703–2706.

98

Kim YC, Kitaura H, Taira T, et al. Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN. Int J Oncol. 2009;35(6):1331–1341.

99

Fine B, Hodakoski C, Koujak S, et al. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science. 2009;325(5945):1261–1265.

100

He L, Ingram A, Rybak AP, et al. Shank-interacting protein-like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells. J Clin Invest. 2010;120(6):2094–2108.

101

He L, Fan C, Kapoor A, et al. α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells. Nat Commun. 2011;2:307.

102

Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol. 1999;11(2):219–225.

103

Planchon SM, Waite KA, Eng C. The nuclear affairs of PTEN. J Cell Sci. 2008;121(Pt 3):249–253.

104

Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269–270.

105

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–1033.

106

Garcia-Cao I, Song MS, Hobbs RM, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell. 2012;149(1):49–62.

107

Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metabol. 2012;15(3):382–394.

108

Vellai T, McCulloch D, Gems D, et al. Effects of sex and insulin/insulin-like growth factor-1 signaling on performance in an associative learning paradigm in Caenorhabditis elegans. Genetics. 2006;174(1):309–316.

109

Wong JT, Kim PTW, Peacock JW, et al. Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Diabetologia. 2007;50(2):395–403.

110

Nakashima N, Sharma PM, Imamura T, et al. The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J Biol Chem. 2000;275(17):12889–12895.

111

Mosser VA, Li Y, Quon MJ. PTEN does not modulate GLUT4 translocation in rat adipose cells under physiological conditions. Biochem Biophys Res Commun. 2001;288(4):1011–1017.

112

Morani F, Phadngam S, Follo C, et al. PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells. J Mol Endocrinol. 2014;53(2):247–258.

113

Horie Y, Suzuki A, Kataoka E, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113(12):1774–1783.

114

Raftopoulou M, Etienne-Manneville S, Self A, et al. Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science. 2004;303(5661):1179–1181.

115

Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280(5369):1614–1617.

116

Park MJ, Kim MS, Park IC, et al. PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res. 2002;62(21):6318–6322.

117

Gu J, Tamura M, Pankov R, et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol. 1999;146(2):389–403.

118

Martin-Belmonte F, Gassama A, Datta A, et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell. 2007;128(2):383–397.

119

Aquila S, Santoro M, Caputo A, et al. The tumor suppressor PTEN as molecular switch node regulating cell metabolism and autophagy: implications in immune system and tumor microenvironment. Cells. 2020;9(7):1725.

120

Lin Z, Huang L, Li SL, et al. PTEN loss correlates with T cell exclusion across human cancers. BMC Cancer. 2021;21:429.

121

Vidotto T, Saggioro FP, Jamaspishvili T, et al. PTEN-deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells. Prostate. 2019;79(9):969–979.

122

Yang Y, Bai Y, He Y, et al. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer. Clin Cancer Res. 2018;24(4):834–846.

123

Kurose K, Gilley K, Matsumoto S, et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet. 2002;32(3):355–357.

124

Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.

125

Trimboli AJ, Cantemir-Stone CZ, Li F, et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature. 2009;461(7267):1084–1091.

126

Bronisz A, Godlewski J, Wallace JA, et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol. 2011;14(2):159–167.

127

Skinner HD, Zheng JZ, Fang J, et al. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1α, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J Biol Chem. 2004;279(44):45643–45651.

128

Shen W, Li HL, Liu L, et al. Expression levels of PTEN, HIF-1α, and VEGF as prognostic factors in ovarian cancer. Eur Rev Med Pharmacol Sci. 2017;21(11):2596–2603.

129

Wen S, Stolarov J, Myers MP, et al. PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci U S A. 2001;98(8):4622–4627.

130

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;156(5):1693–1700.

131

Perren A, Weng LP, Boag AH, et al. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 1999;155(4):1253–1260.

132

Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell. 2005;7(2):193–204.

133

Song MS, Carracedo A, Salmena L, et al. Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell. 2011;144(2):187–199.

134

Liu XS, Song B, Elzey BD, et al. Polo-like kinase 1 facilitates loss of Pten tumor suppressor-induced prostate cancer formation. J Biol Chem. 2011;286(41):35795–35800.

135

Freeman DJ, Li AG, Wei G, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and-independent mechanisms. Cancer Cell. 2003;3(2):117–130.

136

Ogawara Y, Kishishita S, Obata T, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–21850.

137

Zecchin D, Moore C, Michailidis F, et al. Combined targeting of G protein-coupled receptor and EGF receptor signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer. EMBO Mol Med. 2020;12(8):e11987.

138

Owusu-Brackett N, Zhao M, Akcakanat A, et al. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss. Oncotarget. 2020;11(11):969–981.

139

Dent R, Oliveira M, Isakoff SJ, et al. Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2021;189(2):377–386.

140

Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–98.

141

Hartwell LH, Szankasi P, Roberts CJ, et al. Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997;278(5340):1064–1068.

142

Brunen D, Bernards R. Drug therapy: exploiting synthetic lethality to improve cancer therapy. Nat Rev Clin Oncol. 2017;14(6):331–332.

143

O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet. 2017;18(10):613–623.

144

Topatana W, Juengpanich S, Li S, et al. Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation. J Hematol Oncol. 2020;13:118.

145

Doye V, Hurt EC. Genetic approaches to nuclear pore structure and function. Trends Genet. 1995;11(6):235–241.

146

Fece de la Cruz F, Gapp BV, Nijman SMB. Synthetic lethal vulnerabilities of cancer. Annu Rev Pharmacol Toxicol. 2015;55:513–531.

147

Brummelkamp TR, Bernards R. New tools for functional mammalian cancer genetics. Nat Rev Cancer. 2003;3(10):781–789.

148

Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–921.

149

Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–917.

150

Mendes-Pereira AM, Martin SA, Brough R, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6-7):315–322.

151

Liu X, Han EK, Anderson M, et al. Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. Mol Cancer Res. 2009;7(10):1686–1692.

152

McEllin B, Camacho CV, Mukherjee B, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 2010;70(13):5457–5464.

153

Brough R, Frankum JR, Sims D, et al. Functional viability profiles of breast cancer. Cancer Discov. 2011;1(3):260–273.

154

Mendes-Pereira AM, Lord CJ, Ashworth A. NLK is a novel therapeutic target for PTEN deficient tumour cells. PLoS One. 2012;7(10):e47249.

155

Mereniuk TR, El Gendy MAM, Mendes-Pereira AM, et al. Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase. Mol Cancer Therapeut. 2013;12(10):2135–2144.

156

Sadat SMA, Paiva IM, Shire Z, et al. A synthetically lethal nanomedicine delivering novel inhibitors of polynucleotide kinase 3’-phosphatase (PNKP) for targeted therapy of PTEN-deficient colorectal cancer. J Contr Release. 2021;334:335–352.

157

Shire Z, Vakili MR, Morgan TDR, et al. Nanoencapsulation of novel inhibitors of PNKP for selective sensitization to ionizing radiation and irinotecan and induction of synthetic lethality. Mol Pharm. 2018;15(6):2316–2326.

158

Abbotts R, Jewell R, Nsengimana J, et al. Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy. Oncotarget. 2014;5(10):3273–3286.

159

Saglio G, Morotti A, Mattioli G, et al. Rational approaches to the design of therapeutics targeting molecular markers: the case of chronic myelogenous leukemia. Ann N Y Acad Sci. 2004;1028:423–431.

160

Morotti A, Panuzzo C, Crivellaro S, et al. BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia. 2014;28(6):1326–1333.

161

Morotti A, Panuzzo C, Crivellaro S, et al. BCR-ABL inactivates cytosolic PTEN through casein kinase Ⅱ mediated tail phosphorylation. Cell Cycle. 2015;14(7):973–979.

162

McCabe N, Hanna C, Walker SM, et al. Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 2015;75(11):2159–2165.

163

Li K, Yan H, Guo W, et al. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin. Exp Cell Res. 2018;366(1):24–33.

164

Benitez JA, Ma J, D’Antonio M, et al. PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nat Commun. 2017;8:15223.

165

Zhao D, Lu X, Wang G, et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature. 2017;542(7642):484–488.

166

Mathur D, Stratikopoulos E, Ozturk S, et al. PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition. Cancer Discov. 2017;7(4):380–390.

167

Ozturk S, Mathur D, Zhou RW, et al. Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer. Prostate Cancer Prostatic Dis. 2020;23(4):718–723.

168

Tang YC, Ho SC, Tan E, et al. Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer. Breast Cancer Res. 2018;20(1):22.

169

Al-Subhi N, Ali R, Abdel-Fatah T, et al. Targeting ataxia telangiectasia-mutated- and Rad3-related kinase (ATR) in PTEN-deficient breast cancers for personalized therapy. Breast Cancer Res Treat. 2018;169(2):277–286.

170

Chatterjee N, Pazarentzos E, Mayekar MK, et al. Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers. Cell Rep. 2019;28(9):2317–2330.e8.

171

Chen P, Zhao D, Li J, et al. Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-null glioma. Cancer Cell. 2019;35(6):868–884.e6.

172

Ertay A, Liu H, Liu D, et al. WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer. Cell Death Dis. 2020;11(11):1001.

173

Liu Y, Yang EJ, Shi C, et al. Histone acetyltransferase (HAT) P300/CBP inhibitors induce synthetic lethality in PTEN-deficient colorectal cancer cells through destabilizing AKT. Int J Biol Sci. 2020;16(11):1774–1784.

174

Huang A, Garraway LA, Ashworth A, et al. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020;19(1):23–38.

175

Li H, Liu ZY, Wu N, et al. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020;19:107.

176

Li S, Topatana W, Juengpanich S, et al. Development of synthetic lethality in cancer: molecular and cellular classification. Signal Transduct Targeted Ther. 2020;5:241.

177

Ku AA, Hu HM, Zhao X, et al. Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility. Nat Commun. 2020;11:2375.

178

McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell. 2017;168(4):613–628.

179

Martin JD, Cabral H, Stylianopoulos T, et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol. 2020;17(4):251–266.

180

Goldberg MS. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer. 2019;19(10):587–602.

181

Riley RS, June CH, Langer R, et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019;18(3):175–196.

182

Du C, Qi Y, Zhang Y, et al. Epidermal growth factor receptor-targeting peptide nanoparticles simultaneously deliver gemcitabine and olaparib to treat pancreatic cancer with breast cancer 2 (BRCA2) mutation. ACS Nano. 2018;12(11):10785–10796.

183

Ebeid K, Meng X, Thiel KW, et al. Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol. 2018;13(1):72–81.

184

Rolfo C, Giovannetti E. A synthetic lethal bullet. Nat Nanotechnol. 2018;13(1):6–7.

185

Jerde TJ. Phosphatase and tensin homologue: novel regulation by developmental signaling. J Signal Transduct. 2015;2015:282567.

186

Wang X, Jiang X. PTEN: a default gate-keeping tumor suppressor with a versatile tail. Cell Res. 2008;18(8):807–816.

187

Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988–1004.

Genes & Diseases
Pages 2511-2527
Cite this article:
Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes & Diseases, 2023, 10(6): 2511-2527. https://doi.org/10.1016/j.gendis.2022.12.015

254

Views

7

Downloads

7

Crossref

7

Web of Science

7

Scopus

0

CSCD

Altmetrics

Received: 16 October 2022
Revised: 26 December 2022
Accepted: 27 December 2022
Published: 01 February 2023
© 2023 The Authors.

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

Return