EGFR signaling and autophagy dependence for growth, survival, and therapy resistance

Cell Cycle

Volumn 13, Issue 1, 2014, Pages 42-51

  Jutten, Barry ^a   Rouschop, Kasper M A ^a  

^a MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Autophagy; Cancer treatment; EGFR; EGFRvIII; Hypoxia; Metabolic stress; Mutations; Starvation; Treatment resistance

Indexed keywords

BECLIN 1; CHLOROQUINE; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; RAS PROTEIN; STAT3 PROTEIN;

ARTICLE; AUTOPHAGY; CANCER CELL; CANCER RESISTANCE; CANCER STEM CELL; CELL DIFFERENTIATION; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; CONTROLLED STUDY; GENE AMPLIFICATION; GENE OVEREXPRESSION; HOMEOSTASIS; HUMAN; HUMAN CELL; METABOLISM; PROTEIN DOMAIN; SIGNAL TRANSDUCTION; THERAPY RESISTANCE;

AUTOPHAGY; CANCER TREATMENT; EGFR; EGFRVIII; HYPOXIA; METABOLIC STRESS; MUTATIONS; STARVATION; TREATMENT RESISTANCE;

ANTINEOPLASTIC AGENTS; AUTOPHAGY; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; DRUG RESISTANCE, NEOPLASM; HUMANS; NEOPLASMS; RECEPTOR, EPIDERMAL GROWTH FACTOR; SIGNAL TRANSDUCTION;

EID: 84892589371     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.27518     Document Type: Article

References (123)

1. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984; 307: 521-7; PMID:6320011; http://dx.doi.org/10.1038/307521a0 (Pubitemid 14135812)
2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127-37; PMID:11252954; http://dx.doi.org/10.1038/35052073 (Pubitemid 33674041)
3. Lemmon MA, Bu Z, Ladbury JE, Zhou M, Pinchasi D, Lax I, Engelman DM, Schlessinger J. Two EGF molecules contribute additively to stabilization of the EGFR dimer. EMBO J 1997; 16:281-94; PMID:9029149; http://dx.doi.org/10.1093/ emboj/16.2.281 (Pubitemid 27049386)
4. Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 2006; 16: 649-56; PMID:17085050; http://dx.doi.org/10. 1016/j.tcb.2006.10.008 (Pubitemid 44809890)
5. Perez R, Crombet T, de Leon J, Moreno E. A view on EGFR-targeted therapies from the oncogeneaddiction perspective. Front Pharmacol 2013; 4:53; PMID:23637683; http://dx.doi.org/10.3389/fphar.2013.00053
6. Mizushima N. The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 2005; 12(Suppl 2): 1535-41; PMID:16247501; http://dx.doi.org/10.1038/sj.cdd.4401728 (Pubitemid 41553990)
7. King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 1985; 229: 974-6; PMID:2992089; http://dx.doi.org/10.1126/science.2992089 (Pubitemid 16248488)
8. King CR, Kraus MH, Williams LT, Merlino GT, Pastan IH, Aaronson SA. Human tumor cell lines with EGF receptor gene amplification in the absence of aberrant sized mRNAs. Nucleic Acids Res 1985; 13: 8477-86; PMID:3001641; http://dx.doi.org/10.1093/nar/13.23.8477
9. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985; 313: 144-7; PMID:2981413; http://dx.doi.org/10.1038/ 313144a0 (Pubitemid 15192341)
10. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37(Suppl 4):S9-15; PMID:11597399; http://dx.doi.org/10.1016/S0959-8049(01) 00231-3
11. Weinstein IB, Joe A. Oncogene addiction. Cancer Res 2008; 68: 3077-80, discussion 3080; PMID:18451130; http://dx.doi.org/10.1158/0008-5472.CAN-07-3293
12. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction - a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006; 3: 448-57; PMID:16894390; http://dx.doi.org/10.1038/ncponc0558 (Pubitemid 44203817)
13. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337-45; PMID:15269313; http://dx.doi.org/10.1056/NEJMoa033025 (Pubitemid 38944402)
14. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al.; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-smallcell lung cancer. N Engl J Med 2005; 353:123-32; PMID:16014882; http://dx.doi.org/10.1056/NEJMoa050753
15. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, et al. Erlotinib in lung cancer -molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133-44; PMID:16014883; http://dx.doi.org/10.1056/NEJMoa050736 (Pubitemid 41058345)
16. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, 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; 350:2129-39; PMID:15118073; http://dx.doi.org/10.1056/NEJMoa040938 (Pubitemid 38637993)
17. Taron M, Ichinose Y, Rosell R, Mok T, Massuti B, Zamora L, Mate JL, Manegold C, Ono M, Queralt C, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005; 11: 5878-85; PMID:16115929; http://dx.doi.org/10.1158/1078-0432.CCR- 04-2618 (Pubitemid 41170316)
18. Hirsch FR, Varella-Garcia M, Bunn PA Jr., Di Maria MV, Veve R, Bremmes RM, Barón AE, Zeng C, Franklin WA. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21:3798-807; PMID:12953099; http://dx.doi.org/10.1200/JCO.2003.11.069 (Pubitemid 46606235)
19. Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol Ther 2011; 11: 777-92; PMID:21293176; http://dx.doi.org/10.4161/cbt.11.9.15050
20. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7: 169-81; PMID:17318210; http://dx.doi.org/10.1038/nrc2088
21. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008; 105: 2070-5; PMID:18227510; http://dx.doi.org/10.1073/pnas.0709662105 (Pubitemid 351439466)
22. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13:e23-31; PMID:21764376; http://dx.doi.org/10.1016/S1470-2045(11) 70129-2
23. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 2003; 63: 6962-70; PMID:14583498 (Pubitemid 37322983)
24. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 1992; 89: 2965-9; PMID:1557402; http://dx.doi.org/10.1073/pnas.89.7.2965
25. Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A 1990; 87: 8602-6; PMID:2236070; http://dx.doi.org/10.1073/pnas.87.21.8602
26. Yamazaki H, Fukui Y, Ueyama Y, Tamaoki N, Kawamoto T, Taniguchi S, Shibuya M. Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol 1988; 8: 1816-20; PMID:3380099
27. Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009; 16: 748-54; PMID:19324552; http://dx.doi.org/10.1016/j.jocn.2008.12.005
28. Smilek P, Neuwirthova J, Jarkovsky J, Dusek L, Rottenberg J, Kostrica R, Srovnal J, Hajduch M, Drabek J, Klozar J. Epidermal growth factor receptor (EGFR) expression and mutations in the EGFR signaling pathway in correlation with anti-EGFR therapy in head and neck squamous cell carcinomas. Neoplasma 2012; 59: 508-15; PMID:22668015; http://dx.doi.org/10.4149/neo-2012-065
29. Sasaki H, Kawano O, Endo K, Yukiue H, Yano M, Fujii Y. EGFRvIII mutation in lung cancer correlates with increased EGFR copy number. Oncol Rep 2007; 17: 319-23; PMID:17203167
30. Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, Jung BL, McNamara K, Xia H, Glatt KA, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A 2006; 103: 7817-22; PMID:16672372; http://dx.doi.org/ 10.1073/pnas.0510284103
31. Del Vecchio CA, Jensen KC, Nitta RT, Shain AH, Giacomini CP, Wong AJ. Epidermal growth factor receptor variant III contributes to cancer stem cell phenotypes in invasive breast carcinoma. Cancer Res 2012; 72: 2657-71; PMID:22419663; http://dx.doi.org/10.1158/0008-5472.CAN-11-2656
32. Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995; 55: 5536-9; PMID:7585629
33. Weppler SA, Li Y, Dubois L, Lieuwes N, Jutten B, Lambin P, Wouters BG, Lammering G. Expression of EGFR variant vIII promotes both radiation resistance and hypoxia tolerance. Radiother Oncol 2007; 83: 333-9; PMID:17512071; http://dx.doi.org/10.1016/j.radonc.2007.04.025 (Pubitemid 46907978)
34. Golding SE, Morgan RN, Adams BR, Hawkins AJ, Povirk LF, Valerie K. Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells. Cancer Biol Ther 2009; 8:730-8; PMID:19252415; http://dx.doi.org/10.4161/cbt.8.8.7927
35. Learn CA, Hartzell TL, Wikstrand CJ, Archer GE, Rich JN, Friedman AH, Friedman HS, Bigner DD, Sampson JH. Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme. Clin Cancer Res 2004; 10: 3216-24; PMID:15131063; http://dx.doi.org/10.1158/1078-0432.CCR-03-0521 (Pubitemid 38619703)
36. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996; 56: 4509-15; PMID:8813149 (Pubitemid 26330463)
37. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005; 77: 18-24; PMID:16098619; http://dx.doi.org/10.1016/j.radonc.2005.06.038 (Pubitemid 41503384)
38. Wouters BG, van den Beucken T, Magagnin MG, Lambin P, Koumenis C. Targeting hypoxia tolerance in cancer. Drug Resist Updat 2004; 7: 25-40; PMID:15072769; http://dx.doi.org/10.1016/j.drup.2003.12.004 (Pubitemid 38453834)
39. Theys J, Jutten B, Dubois L, Rouschop KM, Chiu RK, Li Y, Paesmans K, Lambin P, Lammering G, Wouters BG. The deletion mutant EGFRvIII significantly contributes to stress resistance typical for the tumour microenvironment. Radiother Oncol 2009; 92: 399-404; PMID:19616331; http://dx.doi.org/10.1016/j. radonc.2009.06.017
40. Bigner SH, Humphrey PA, Wong AJ, Vogelstein B, Mark J, Friedman HS, Bigner DD. Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 1990; 50: 8017-22; PMID:2253244
41. Pandita A, Aldape KD, Zadeh G, Guha A, James CD. Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR. Genes Chromosomes Cancer 2004; 39: 29-36; PMID:14603439; http://dx.doi.org/10.1002/ gcc.10300 (Pubitemid 37475250)
42. Stockhausen MT, Broholm H, Villingshøj M, Kirchhoff M, Gerdes T, Kristoffersen K, Kosteljanetz M, Spang-Thomsen M, Poulsen HS. Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme. Exp Cell Res 2011; 317: 1513-26; PMID:21514294; http://dx.doi.org/10.1016/j.yexcr.2011.04.001
43. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 2007; 25: 2288-94; PMID:17538175; http://dx.doi.org/10.1200/JCO.2006.08.0705 (Pubitemid 46954657)
44. Montano N, Cenci T, Martini M, D'Alessandris QG, Pelacchi F, Ricci-Vitiani L, Maira G, De Maria R, Larocca LM, Pallini R. Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia 2011; 13: 1113-21; PMID:22241957
45. Mazzoleni S, Politi LS, Pala M, Cominelli M, Franzin A, Sergi Sergi L, Falini A, De Palma M, Bulfone A, Poliani PL, et al. Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res 2010; 70: 7500-13; PMID:20858720; http://dx.doi.org/ 10.1158/0008-5472.CAN-10-2353
46. Martinez R, Rohde V, Schackert G. Different molecular patterns in glioblastoma multiforme subtypes upon recurrence. J Neurooncol 2010; 96:321-9; PMID:19644652; http://dx.doi.org/10.1007/s11060-009-9967-4
47. Kelly JJ, Stechishin O, Chojnacki A, Lun X, Sun B, Senger DL, Forsyth P, Auer RN, Dunn JF, Cairncross JG, et al. Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens. Stem Cells 2009; 27: 1722-33; PMID:19544433; http://dx.doi.org/10.1002/stem.98
48. Griffero F, Daga A, Marubbi D, Capra MC, Melotti A, Pattarozzi A, Gatti M, Bajetto A, Porcile C, Barbieri F, et al. Different response of human glioma tumorinitiating cells to epidermal growth factor receptor kinase inhibitors. J Biol Chem 2009; 284: 7138-48; PMID:19147502; http://dx.doi.org/10.1074/jbc. M807111200
49. Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S, Nakashima S, Kunisada T, Iwama T. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 2008; 283: 10958-66; PMID:18292095; http://dx.doi.org/10.1074/jbc.M704205200
50. Ma L, Zhang G, Miao XB, Deng XB, Wu Y, Liu Y, Jin ZR, Li XQ, Liu QZ, Sun DX, et al. Cancer stem-like cell properties are regulated by EGFR/AKT/β-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma. FEBS J 2013; 280: 2027-41; PMID:23461856; http://dx.doi.org/10.1111/febs.12226
51. Clark PA, Iida M, Treisman DM, Kalluri H, Ezhilan S, Zorniak M, Wheeler DL, Kuo JS. Activation of multiple ERBB family receptors mediates glioblastoma cancer stem-like cell resistance to EGFRtargeted inhibition. Neoplasia 2012; 14: 420-8; PMID:22745588
52. Li G, Mitra SS, Monje M, Henrich KN, Bangs CD, Nitta RT, Wong AJ. Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas. J Neurooncol 2012; 108: 395-402; PMID:22382786; http://dx.doi.org/10.1007/s11060-012-0842-3
53. Liu XJ, Wu WT, Wu WH, Yin F, Ma SH, Qin JZ, Liu XX, Liu YN, Zhang XY, Li P, et al. A minority subpopulation of CD133(+) /EGFRvIII(+) /EGFR(-) cells acquires stemness and contributes to gefitinib resistance. CNS Neurosci Ther 2013; 19:494-502; PMID:23575351; http://dx.doi.org/10.1111/cns.12092
54. Kolch W, Pitt A. Functional proteomics to dissect tyrosine kinase signalling pathways in cancer. Nat Rev Cancer 2010; 10: 618-29; PMID:20720570; http://dx.doi.org/10.1038/nrc2900
55. Edinger AL, Thompson CB. Defective autophagy leads to cancer. Cancer Cell 2003; 4: 422-4; PMID:14706333; http://dx.doi.org/10.1016/S1535-6108(03)00306-4 (Pubitemid 38050038)
56. Levine B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 2005; 120: 159-62; PMID:15680321 (Pubitemid 40174758)
57. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005; 169: 425-34; PMID:15866887; http://dx.doi.org/10.1083/jcb.200412022 (Pubitemid 40686693)
58. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature 2004; 432:1032-6; PMID:15525940; http://dx.doi.org/10. 1038/nature03029 (Pubitemid 40052234)
59. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51-64; PMID:16843265; http://dx.doi.org/10.1016/j.ccr.2006.06.001
60. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 2010; 120:127-41; PMID:20038797; http://dx.doi.org/10.1172/JCI40027
61. Jutten B, Keulers TG, Schaaf MB, Savelkouls K, Theys J, Span PN, Vooijs MA, Bussink J, Rouschop KM. EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival. Radiother Oncol 2013; 108: 479-83; PMID:23891088; http://dx.doi.org/10.1016/j.radonc.2013.06.033
62. Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, Kinch L, Koduru P, Christudass CS, Veltri RW, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013; 154:1269-84; PMID:24034250; http://dx.doi.org/10.1016/j.cell.2013.08.015
63. Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 2008; 13: 385-93; PMID:18455122; http://dx.doi.org/10.1016/j.ccr.2008.03. 015 (Pubitemid 351609444)
64. Li X, Fan Z. The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res 2010; 70: 5942-52; PMID:20634405; http://dx.doi.org/10.1158/0008-5472.CAN-10-0157
65. Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, Ge W, Feng L, Lin X, Wang X, et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One 2011; 6:e18691; PMID:21655094; http://dx.doi.org/10.1371/journal.pone.0018691
66. Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 2010; 6: 1066-77; PMID:20864811; http://dx.doi.org/10.4161/auto.6.8.13366
67. Wolf-Yadlin A, Hautaniemi S, Lauffenburger DA, White FM. Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks. Proc Natl Acad Sci U S A 2007; 104:5860-5; PMID:17389395; http://dx.doi.org/10.1073/pnas.0608638104 (Pubitemid 47175624)
68. Huang PH, Mukasa A, Bonavia R, Flynn RA, Brewer ZE, Cavenee WK, Furnari FB, White FM. Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci U S A 2007; 104: 12867-72; PMID:17646646; http://dx.doi.org/10.1073/pnas. 0705158104 (Pubitemid 47255246)
69. Moscatello DK, Holgado-Madruga M, Emlet DR, Montgomery RB, Wong AJ. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem 1998; 273: 200-6; PMID:9417065; http://dx.doi.org/10.1074/jbc.273.1.200 (Pubitemid 28042194)
70. 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: 2-11; PMID:22025673; http://dx.doi.org/10.1128/MCB.06159-11
71. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132-41; PMID:21258367; http://dx.doi.org/10.1038/ncb2152
72. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009; 20:1981-91; PMID:19211835; http://dx.doi.org/10.1091/mbc.E08-12-1248
73. Jung CH, Seo M, Otto NM, Kim DH. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 2011; 7: 1212-21; PMID:21795849; http://dx.doi.org/10.4161/auto.7.10.16660
74. Pike LR, Singleton DC, Buffa F, Abramczyk O, Phadwal K, Li JL, Simon AK, Murray JT, Harris AL. Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival. Biochem J 2013; 449: 389-400; PMID:23078367; http://dx.doi.org/10.1042/BJ20120972
75. Schaaf MB, Cojocari D, Keulers TG, Jutten B, Starmans MH, de Jong MC, Begg AC, Savelkouls KG, Bussink J, Vooijs M, et al. The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia. Radiother Oncol 2013; 108:529-34; PMID:23849170; http://dx.doi.org/10.1016/j.radonc.2013.06.015
76. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7: 295-308; PMID:17384584; http://dx.doi.org/10.1038/nrc2109 (Pubitemid 46480970)
77. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 2011; 25: 460-70; PMID:21317241; http://dx.doi.org/10.1101/gad.2016311
78. Kim MJ, Woo SJ, Yoon CH, Lee JS, An S, Choi YH, Hwang SG, Yoon G, Lee SJ. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem 2011; 286:12924-32; PMID:21300795; http://dx.doi.org/10.1074/jbc.M110.138958
79. Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, Debnath J. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 2011; 22: 165-78; PMID:21119005; http://dx.doi.org/10.1091/mbc.E10-06-0500
80. Alexandrova AY, Kopnin PB, Vasiliev JM, Kopnin BP. ROS up-regulation mediates Ras-induced changes of cell morphology and motility. Exp Cell Res 2006; 312: 2066-73; PMID:16624288; http://dx.doi.org/10.1016/j.yexcr.2006.03.004 (Pubitemid 43850931)
81. Kopnin PB, Agapova LS, Kopnin BP, Chumakov PM. Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability. Cancer Res 2007; 67: 4671-8; PMID:17510393; http://dx.doi.org/10.1158/0008-5472.CAN-06-2466 (Pubitemid 46910172)
82. Ren Z, Mao X, Mertens C, Krishnaraj R, Qin J, Mandal PK, Romanowski MJ, McMurray JS, Chen X. Crystal structure of unphosphorylated STAT3 core fragment. Biochem Biophys Res Commun 2008; 374: 1-5; PMID:18433722; http://dx.doi.org/10. 1016/j.bbrc.2008.04.049
83. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994; 264: 95-8; PMID:8140422; http://dx.doi.org/10.1126/ science.8140422 (Pubitemid 24144493)
84. Boulton TG, Zhong Z, Wen Z, Darnell JE Jr., Stahl N, Yancopoulos GD. STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. Proc Natl Acad Sci U S A 1995; 92:6915-9; PMID:7624343; http://dx.doi.org/10.1073/pnas.92.15.6915
85. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3: 651-62; PMID:12209125; http://dx.doi.org/10.1038/nrm909 (Pubitemid 34987786)
86. Shen S, Niso-Santano M, Adjemian S, Takehara T, Malik SA, Minoux H, Souquere S, Mariño G, Lachkar S, Senovilla L, et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell 2012; 48: 667-80; PMID:23084476; http://dx.doi.org/10.1016/j.molcel.2012.09.013
87. Niso-Santano M, Shen S, Adjemian S, Malik SA, Mariño G, Lachkar S, Senovilla L, Kepp O, Galluzzi L, Maiuri MC, et al. Direct interaction between STAT3 and EIF2AK2 controls fatty acid-induced autophagy. Autophagy 2013; 9: 415-7; PMID:23221979; http://dx.doi.org/10.4161/auto.22910
88. Schwarze MM, Hawley RG. Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res 1995; 55: 2262-5; PMID:7757973
89. Tai WT, Shiau CW, Chen HL, Liu CY, Lin CS, Cheng AL, Chen PJ, Chen KF. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells. Cell Death Dis 2013; 4:e485; PMID:23392173; http://dx.doi.org/10.1038/cddis.2013.18
90. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009; 11: 385-96; PMID:19270696; http://dx.doi.org/10.1038/ncb1846
91. Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 2007; 3: 561-8; PMID:17643073 (Pubitemid 350060052)
92. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003; 100:15077-82; PMID:14657337; http://dx.doi.org/10.1073/pnas.2436255100 (Pubitemid 37518019)
93. Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999; 59: 59-65; PMID:10395800; http://dx.doi.org/10.1006/geno.1999.5851 (Pubitemid 29339873)
94. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672-6; PMID:10604474; http://dx.doi.org/10.1038/45257 (Pubitemid 129516338)
95. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809-20; PMID:14638851 (Pubitemid 38063704)
96. Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19: 5360-72; PMID:18843052; http://dx.doi.org/10.1091/mbc.E08-01- 0080
97. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122: 927-39; PMID:16179260; http://dx.doi.org/10.1016/j. cell.2005.07.002 (Pubitemid 41345209)
98. Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, Czernin J, Shyy JY, Watson AD, Phelps M, et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci U S A 2009; 106: 12932-7; PMID:19625624; http://dx.doi.org/10.1073/pnas. 0906606106
99. Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, Zhu S, Gu Y, Villa GR, Akhavan D, et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 2013; 17: 1000-8; PMID:23707073; http://dx.doi.org/10.1016/j.cmet.2013.04.013
100. Rasbach KA, Schnellmann RG. Signaling of mitochondrial biogenesis following oxidant injury. J Biol Chem 2007; 282: 2355-62; PMID:17116659 (Pubitemid 47076768)
101. 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: 7059-71; PMID:15282306; http://dx.doi.org/10.1128/MCB.24.16.7059-7071.2004 (Pubitemid 39014433)
102. Demory ML, Boerner JL, Davidson R, Faust W, Miyake T, Lee I, Hüttemann M, Douglas R, Haddad G, Parsons SJ. Epidermal growth factor receptor translocation to the mitochondria: regulation and effect. J Biol Chem 2009; 284: 36592-604; PMID:19840943; http://dx.doi.org/10.1074/jbc.M109.000760
103. Cao X, Zhu H, Ali-Osman F, Lo HW. EGFR and EGFRvIII undergo stress-and EGFR kinase inhibitorinduced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis. Mol Cancer 2011; 10:26; PMID:21388543; http://dx.doi.org/10.1186/1476-4598-10-26
104. Cvrljevic AN, Akhavan D, Wu M, Martinello P, Furnari FB, Johnston AJ, Guo D, Pike L, Cavenee WK, Scott AM, et al. Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism. J Cell Sci 2011; 124: 2938-50; PMID:21878501; http://dx.doi.org/10. 1242/jcs.083295
105. Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, Kavanagh BD, Contessa JN, Rorrer WK, Chen PB. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 1997; 15: 1191-7; PMID:9294612; http://dx.doi.org/10. 1038/sj.onc.1201275 (Pubitemid 27429622)
106. Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Kehlbach R, Rodemann HP. Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654. FEBS Lett 2010; 584: 3878-84; PMID:20692258; http://dx.doi.org/10.1016/j.febslet.2010.08.005
107. Harris AL. Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38-47; PMID:11902584; http://dx.doi.org/10.1038/nrc704 (Pubitemid 37328806)
108. Rouschop KM, Dubois L, Schaaf MB, van den Beucken T, Lieuwes N, Keulers TG, Savelkouls KG, Bussink J, van der Kogel AJ, Koritzinsky M, et al. Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction. Radiother Oncol 2011; 99: 385-91; PMID:21665307; http://dx.doi.org/10.1016/j.radonc.2011.05.047
109. Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M, Wouters BG. PERK/eIF2aa signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc Natl Acad Sci U S A 2013; 110: 4622-7; PMID:23471998; http://dx.doi.org/10.1073/pnas.1210633110
110. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck-a systematic review and meta-analysis. Radiother Oncol 2011; 100: 22-32; PMID:21511351; http://dx.doi.org/10.1016/j.radonc.2011. 03.004
111. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM. Hypoxiainduced autophagy is mediated through hypoxiainducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 2009; 29:2570-81; PMID:19273585; http://dx.doi.org/10.1128/MCB.00166-09
112. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717-21; PMID:11099404; http://dx.doi.org/10. 1126/science.290.5497.1717 (Pubitemid 32004796)
113. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008; 283: 10892-903; PMID:18281291; http://dx.doi.org/10.1074/jbc.M800102200
114. Papandreou I, Lim AL, Laderoute K, Denko NC. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 2008; 15:1572-81; PMID:18551130; http://dx.doi.org/10.1038/cdd. 2008.84
115. Rouschop KM, Ramaekers CH, Schaaf MB, Keulers TG, Savelkouls KG, Lambin P, Koritzinsky M, Wouters BG. Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother Oncol 2009; 92: 411-6; PMID:19616335; http://dx.doi.org/10.1016/j.radonc.2009.06.029
116. Stegeman H, Kaanders JH, van der Kogel AJ, Iida M, Wheeler DL, Span PN, Bussink J. Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR-inhibition and radiotherapy sensitivity in head and neck cancer models. Radiother Oncol 2013; 106: 383-9; PMID:23453541; http://dx.doi.org/10.1016/j.radonc.2013.02.001
117. Gong C, Bauvy C, Tonelli G, Yue W, Deloménie C, Nicolas V, Zhu Y, Domergue V, Marin-Esteban V, Tharinger H, et al. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stemlike/progenitor cells. Oncogene 2013; 32: 2261-72, 1-11; PMID:22733132; http://dx.doi.org/10.1038/onc. 2012.252
118. Galavotti S, Bartesaghi S, Faccenda D, Shaked-Rabi M, Sanzone S, McEvoy A, Dinsdale D, Condorelli F, Brandner S, Campanella M, et al. The autophagyassociated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene 2013; 32: 699-712; PMID:22525272; http://dx.doi.org/10.1038/onc.2012.111
119. Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005; 11: 397-405; PMID:15671571 (Pubitemid 40075820)
120. Sequist LV, Lynch TJ. EGFR tyrosine kinase inhibitors in lung cancer: an
121. 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: 354-61; PMID:23769318; http://dx.doi.org/10.1016/j.lungcan.2013.05. 012
122. 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: 693-702; PMID:23575415; http://dx.doi.org/10.1097/JTO.0b013e31828c7210
123. Shen J, Zheng H, Ruan J, Fang W, Li A, Tian G, Niu X, Luo S, Zhao P. Autophagy inhibition induces enhanced proapoptotic effects of ZD6474 in glioblastoma. Br J Cancer 2013; 109: 164-71; PMID:23799852; http://dx.doi.org/ 10.1038/bjc.2013.306