Tumor Biology

, Volume 35, Issue 12, pp 11701–11709 | Cite as

EGFR inhibitors and autophagy in cancer treatment

  • Jie Cui
  • Yun-Feng Hu
  • Xie-Min Feng
  • Tao Tian
  • Ya-Huan Guo
  • Jun-Wei Ma
  • Ke-Jun Nan
  • Hong-Yi Zhang


Epidermal growth factor receptor (EGFR) inhibitor treatment is a strategy for cancer therapy. However, innate and acquired resistance is a major obstacle of the efficacy. Autophagy is a self-digesting process in cells, which is considered to be associated with anti-cancer drug resistance. The activation of EGFR can regulate autophagy through multiple signal pathways. EGFR inhibitors can induce autophagy, but the specific function of the induction of autophagy by EGFR inhibitors remains biphasic. On the one hand, autophagy induced by EGFR inhibitors acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR inhibitors. On the other hand, a high level of autophagy after treatment of EGFR inhibitors can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR inhibitors with an autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficacy of EGFR inhibitors in the treatment of cancer patients.


EGFR-TKI Gefitinib Erlotinib Cetuximab EGFR Autophagy Resistance 



Autophagy-related genes


Class III phosphatidylinositol-3 kinase


Class I phosphoinositide 3-kinase


Vesicular protein sorting 34


Epidermal growth factor receptor


Bcl-2/adenovirus E1B 19-kDa interacting protein 3


Cytosolic microtubule-associated protein light chain 3


AMP-activated protein kinase


Mitogen-activated protein kinase


Extracellular signal-related kinase


Receptor tyrosine kinases


Tuberous sclerosis protein 2


Sodium/glucose cotransporter 1


S6 kinase 1


4E-binding protein 1


EGFR tyrosine kinases


Non-small cell lung cancer


Small cell lung cancer






Erlotinib resistant


Gefitinib resistant


Acidic vesicular organelle


Damage-regulated autophagy modulator 1


NADPH oxidase 4


Phosphatase with tensin homologue


Hypoxia-inducible factor 1-α


Advanced colorectal cancer


Progress-free survival


Objective response rate



We would like to offer special thanks to the Department of Oncology, Yanan University Affiliated Hospital, and the Center of Molecular Biology of Xi’an Jiaotong University for their help with the manuscript. The study is supported by the national specialised research fund for the doctor degree program of institute (Grant No 20110201120061) and the National Science Foundation for Young Scholars of China (Grant No 81301909).


  1. 1.
    De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.PubMedCrossRefGoogle Scholar
  2. 2.
    Klionsky DJ. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4(6):740–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12(9):814–22.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Hu YL, Jahangiri A, Delay M, Aghi MK. Tumor cell autophagy as an adaptive response mediating resistance to treatments like anti-angiogenic therapy. Cancer Res. 2012;72(17):4294–9.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005;17(2):158–66.PubMedCrossRefGoogle Scholar
  6. 6.
    Sonenberg N, Hay N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Dowling R, Topisirovic I, Fonseca B, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 1804;2010:433–9.Google Scholar
  8. 8.
    Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32(1):2–11.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie. 2008;90(2):313–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Fu LL, Cheng Y, Liu B. Beclin-1: autophagic regulator and therapeutic target in cancer. Int J Biochem Cell Biol. 2013;45(5):921–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–68.PubMedCrossRefGoogle Scholar
  12. 12.
    Li L, Chen Y, Gibson SB. Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal. 2013;25(1):50–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev. 2011;25(19):1999–2010.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6(12):1221–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304(5676):1500–2.PubMedCrossRefGoogle Scholar
  16. 16.
    Kubisch J, Türei D, Földvári-Nagy L, Dunai ZA, Zsákai L, Varga ML, et al. Complex regulation of autophagy in cancer—integrated approaches to discover the networks that hold a double-edged sword. Semin Cancer Biol. 2013;23(4):252–61.PubMedCrossRefGoogle Scholar
  17. 17.
    Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wells A. EGF receptor. Int J Biochem Cell Biol. 1999;31(6):637–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Vogt PK, Gymnopoulos M, Hart JR. PI3-kinase and cancer: changing accents. Curr Opin Genet Dev. 2009;19(1):12–7.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–510.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science. 2012;338(6109):956–9.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Santi SA, Lee H. Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells. PLoS One. 2011;6(1):e14614.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell. 2013;154(6):1269–84.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Furuta S, Hidaka E, Ogata A, Yokota S, Kamata T. Ras is involved in the negative control of autophagy through the class I PI3-kinase. Oncogene. 2004;23(22):3898–904.PubMedCrossRefGoogle Scholar
  26. 26.
    Ogier-Denis E, Pattingre S, El Benna J, Codogno P. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem. 2000;275(50):39090–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Pattingre S, Bauvy C, Codogno P. Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem. 2003;278(19):16667–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Corcelle E, Nebout M, Bekri S, Gauthier N, Hofman P, Poujeol P, et al. Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer Res. 2006;66(13):6861–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Stevens C, Lin Y, Harrison B, Burch L, Ridgway RA, Sansom O, et al. Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. J Biol Chem. 2009;284(1):334–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 2008;13(5):385–93.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Boerner JL, Demory ML, Silva C, Parsons SJ. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol. 2004;24(16):7059–71.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Yao Y, Wang G, Li Z, Yan B, Guo Y, Jiang X, et al. Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability. Acta Biochim Biophys Sin (Shanghai). 2010;42(11):763–70.CrossRefGoogle Scholar
  33. 33.
    Yue X, Song W, Zhang W, Chen L, Xi Z, Xin Z, et al. Mitochondrially localized EGFR is subjected to autophagic regulation and implicated in cell survival. Autophagy. 2008;4(5):641–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Dreier A, Barth S, Goswami A, Weis J. Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance? Tumour Biol. 2012;33(1):85–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Cao X, Zhu H, Ali-Osman F, Lo HW. EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis. Mol Cancer. 2011;10:26.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Khalil MY, Grandis JR, Shin DM. Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. Expert Rev Anticancer Ther. 2003;3(3):367–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Herbst RS, Sandler AB. Overview of the current status of human epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer. 2004;6 Suppl 1:S7–S19.PubMedCrossRefGoogle Scholar
  38. 38.
    Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;12:2237–46.CrossRefGoogle Scholar
  39. 39.
    Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22(16):3238–47.PubMedCrossRefGoogle Scholar
  40. 40.
    Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527–37.PubMedCrossRefGoogle Scholar
  41. 41.
    Shepherd FA, Pereira RJ, Ciuleanu T, Tan EH, Hirsh V, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.PubMedCrossRefGoogle Scholar
  43. 43.
    Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10(11):760–74.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.PubMedCrossRefGoogle Scholar
  45. 45.
    Patel MR, Jay-Dixon J, Sadiq AA, Jacobson BA, Kratzke RA. Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC. J Thorac Oncol. 2013;8(9):1142–7.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Xu Y, Liu H, Chen J, Zhou Q. Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib. Cancer Biol Ther. 2010;9(8):572–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Costanzo R, Piccirillo MC, Sandomenico C, Carillio G, Montanino A, Daniele G, et al. Gefitinib in non small cell lung cancer. J Biomed Biotechnol. 2011;2011:815269.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Jiang Z, Li C, Li F, Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis. PLoS One. 2013;8(2):e56205.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Bourhis J, Lefebvre JL, Vermorken JB. Cetuximab in the management of locoregionally advanced head and neck cancer: expanding the treatment options? Eur J Cancer. 2010;46(11):1979–89.PubMedCrossRefGoogle Scholar
  50. 50.
    Qiu LX, Mao C, Zhang J, Zhu XD, Liao RY, Xue K, et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer. 2010;46(15):2781–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One. 2011;6(6):e18691.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Zou Y, Ling YH, Sironi J, Schwartz EL, Perez-Soler R, Piperdi B. The autophagy inhibitor chloroquine overcomes the innate resistance of wild-type EGFR non-small-cell lung cancer cells to erlotinib. J Thorac Oncol. 2013;8(6):693–702.PubMedCrossRefGoogle Scholar
  53. 53.
    Sakuma Y, Matsukuma S, Nakamura Y, Yoshihara M, Koizume S, Sekiguchi H, et al. Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells. Lab Investig. 2013;93(10):1137–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Moreira-Leite FF, Harrison LR, Mironov A, Roberts RA, Dive C. Inducible EGFR T790M-mediated gefitinib resistance in non-small cell lung cancer cells does not modulate sensitivity to PI103 provoked autophagy. J Thorac Oncol. 2010;5(6):765–77.PubMedCrossRefGoogle Scholar
  55. 55.
    Lee JG, Wu R. Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer. PLoS One. 2012;7(10):e48532.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Li YY, Lam SK, Mak JC, Zheng CY, Ho JC. Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer. Lung Cancer. 2013;81(3):354–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Crighton D, Wilkinson S. O’Prey, Syed N, Smith P, Harrison PR, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126(1):121–34.PubMedCrossRefGoogle Scholar
  58. 58.
    Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to p53 and programmed cell death. Autophagy. 2007;3(1):72–4.PubMedCrossRefGoogle Scholar
  59. 59.
    O’Prey J, Skommer J, Wilkinson S, Ryan KM. Analysis of DRAM-related proteins reveals evolutionarily conserved and divergent roles in the control of autophagy. Cell Cycle. 2009;8(14):2260–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008;10(6):676–87.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Bokobza SM, Jiang Y, Weber AM, Devery AM, Ryan AJ. Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells. Oncotarget. 2014;5(13):4765–78.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Sobhakumari A, Schickling BM, Love-Homan L, Raeburn A, Fletcher EV, Case AJ, et al. NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells. Toxicol Appl Pharmacol. 2013;272(3):736–45.PubMedCrossRefGoogle Scholar
  63. 63.
    Dragowska WH, Weppler SA, Wang JC, Wong LY, Kapanen AI, Rawji JS, et al. Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer. PLoS One. 2013;8(10):e76503.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Eimer S, Belaud-Rotureau MA, Airiau K, Jeanneteau M, Laharanne E, Véron N, et al. Autophagy inhibition cooperates with erlotinib to induce glioblastoma cell death. Cancer Biol Ther. 2011;11(12):1017–27.PubMedCrossRefGoogle Scholar
  65. 65.
    Fung C, Chen X, Grandis JR, Duvvuri U. EGFR tyrosine kinase inhibition induces autophagy in cancer cells. Cancer Biol Ther. 2012;13(14):1417–24.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Gorzalczany Y, Gilad Y, Amihai D, Hammel I, Sagi-Eisenberg R, Merimsky O. Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: a beneficial strategy to combat non-small cell lung cancer. Cancer Lett. 2011;310(2):207–15.PubMedCrossRefGoogle Scholar
  67. 67.
    Chang CY, Kuan YH, Ou YC, Li JR, Wu CC, Pan PH, et al. Autophagy contributes to gefitinib-induced glioma cell growth inhibition. Exp Cell Res. 2014;327(1):102–12.PubMedCrossRefGoogle Scholar
  68. 68.
    Schmid K, Bago-Horvath Z, Berger W, Haitel A, Cejka D, Werzowa J, et al. Dual inhibition of EGFR and mTOR pathways in small cell lung cancer. Br J Cancer. 2010;103(5):622–62.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Xu Z, Hang J, Hu J, Gao B. Gefitinib, an EGFR tyrosine kinase inhibitor, activates autophagy through AMPK in human lung cancer cells. J BUON. 2014;19(2):466–73.PubMedGoogle Scholar
  70. 70.
    La Monica S, Galetti M, Alfieri RR, Cavazzoni A, Ardizzoni A, Tiseo M, et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol. 2009;78(5):460–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J Thorac Oncol. 2012;7(10):1602–8.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Xinqun L, Zhen F. The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/Vps34 complex. Cancer Res. 2010;70(14):5942–52.CrossRefGoogle Scholar
  73. 73.
    Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy. 2010;6(8):1066–77.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Guo GF, Jiang WQ, Zhang B, Cai YC, Xu RH, Chen XX, et al. Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer. World J Gastroenterol. 2011;17(43):4779–86.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Jie Cui
    • 1
    • 2
  • Yun-Feng Hu
    • 2
  • Xie-Min Feng
    • 2
  • Tao Tian
    • 1
  • Ya-Huan Guo
    • 4
  • Jun-Wei Ma
    • 2
  • Ke-Jun Nan
    • 1
  • Hong-Yi Zhang
    • 1
    • 3
  1. 1.Department of OncologyThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anPeople’s Republic of China
  2. 2.Department of OncologyYanan University Affiliated HospitalYan’anPeople’s Republic of China
  3. 3.Department of UrologyYanan University Affiliated HospitalYan’anPeople’s Republic of China
  4. 4.Department of OncologyShaanxi Province Cancer HospitalXi’anPeople’s Republic of China

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