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Signaling cross-talk in the resistance to HER family receptor targeted therapy

Oncogene volume 33, pages 1073–1081 (2014)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) have an important role in the initiation and progression of various types of cancer. Inhibitors targeting these receptor tyrosine kinases are some of the most successful targeted anticancer drugs widely used for cancer treatment; however, cancer cells have mechanisms of intrinsic and acquired drug resistance that pose as major obstacles in drug efficacy. Extensive studies from both clinical and laboratory research have identified several molecular mechanisms underlying resistance. Among them is the role of signaling cross-talk between the EGFR/HER2 and other signaling pathways. In this review, we focus particularly on this signaling cross-talk at the receptor, mediator and effector levels, and further discuss alternative approaches to overcome resistance. In addition to well-recognized signaling cross-talk involved in the resistance, we also introduce the cross-talk between EGFR/HER2-mediated pathways and pathways triggered by other types of receptors, including those of the Notch, Wnt and TNFR/IKK/NF-κB pathways, and discuss the potential role of targeting this cross-talk to sensitize cells to EGFR/HER2 inhibitors.

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References

  1. Dhomen NS, Mariadason J, Tebbutt N, Scott AM . Therapeutic targeting of the epidermal growth factor receptor in human cancer. Crit Rev Oncog 2012; 17: 31–50.

    PubMed  Google Scholar 

  2. Baselga J, Arteaga CL . Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005; 23: 2445–2459.

    CAS  PubMed  Google Scholar 

  3. Rimawi MF, Shetty PB, Weiss HL, Schiff R, Osborne CK, Chamness GC et al. Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes. Cancer 2010; 116: 1234–1242.

    PubMed  Google Scholar 

  4. Shigematsu H, Gazdar AF . Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006; 118: 257–262.

    CAS  PubMed  Google Scholar 

  5. Gan HK, Kaye AH, Luwor RB . The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009; 16: 748–754.

    CAS  PubMed  Google Scholar 

  6. Bronte G, Terrasi M, Rizzo S, Sivestris N, Ficorella C, Cajozzo M et al. EGFR genomic alterations in cancer: prognostic and predictive values. Front Biosci (Elite Ed) 2011; 3: 879–887.

    Google Scholar 

  7. Sharma MR, Schilsky RL . GI cancers in 2010: new standards and a predictive biomarker for adjuvant therapy. Nat Rev Clin Oncol 2011; 8: 70–72.

    CAS  PubMed  Google Scholar 

  8. Abramson V, Arteaga CL . New strategies in HER2-overexpressing breast cancer: many combinations of targeted drugs available. Clin Cancer Res 2011; 17: 952–958.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sharma SV, Fischbach MA, Haber DA, Settleman J . ‘Oncogenic shock’: explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 2006; 12: 4392s–4395s.

    CAS  PubMed  Google Scholar 

  10. 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: 2129–2139.

    CAS  PubMed  Google Scholar 

  11. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.

    CAS  PubMed  Google Scholar 

  12. Sequist LV, Lynch TJ . EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med 2008; 59: 429–442.

    CAS  PubMed  Google Scholar 

  13. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK . Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16: 15–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L . Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012; 9: 16–32.

    CAS  Google Scholar 

  15. Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W . New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res 2011; 17: 5530–5537.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hynes NE, MacDonald G . ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 2009; 21: 177–184.

    CAS  PubMed  Google Scholar 

  17. Burgess AW . EGFR family: structure physiology signalling and therapeutic targets. Growth Factors 2008; 26: 263–274.

    CAS  PubMed  Google Scholar 

  18. Yarden Y, Sliwkowski MX . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–137.

    CAS  PubMed  Google Scholar 

  19. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008; 455: 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353: 2135–2147.

    CAS  PubMed  Google Scholar 

  21. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68: 6084–6091.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 2009; 106: 19503–19508.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 2012; 44: 852–860.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M et al. An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2012; 19: 279–290.

    PubMed  PubMed Central  Google Scholar 

  25. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2012; 2: 922–933.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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: 1039–1043.

    CAS  PubMed  Google Scholar 

  27. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007; 104: 20932–20937.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY . Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 2007; 13: 2795–2803.

    CAS  PubMed  Google Scholar 

  29. Kono SA, Marshall ME, Ware KE, Heasley LE . The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 2009; 12: 95–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C et al. A molecularly annotated platform of patient-derived xenografts (‘xenopatients’) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 2011; 1: 508–523.

    CAS  PubMed  Google Scholar 

  31. Cappuzzo F, Varella-Garcia M, Finocchiaro G, Skokan M, Gajapathy S, Carnaghi C et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 2008; 99: 83–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG, Weiser MR . HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res 2011; 17: 472–482.

    CAS  PubMed  Google Scholar 

  33. Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S et al. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 2010; 70: 299–308.

    CAS  PubMed  Google Scholar 

  34. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M . Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93: 1852–1857.

    CAS  PubMed  Google Scholar 

  35. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ et al. Trastuzumab-induced HER reprogramming in ‘resistant’ breast carcinoma cells. Cancer Res 2009; 69: 2191–2194.

    CAS  PubMed  Google Scholar 

  36. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G et al. Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 2010; 18: 423–435.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Herbst RS, Heymach JV, Lippman SM . Lung cancer. N Engl J Med 2008; 359: 1367–1380.

    CAS  PubMed  Google Scholar 

  39. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26: 5705–5712.

    CAS  PubMed  Google Scholar 

  40. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359: 1757–1765.

    CAS  PubMed  Google Scholar 

  41. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486: 532–536.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012; 486: 537–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ercan D, Xu C, Yanagita M, Monast CS, Pratilas CA, Montero J et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov 2012; 2: 934–947.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci USA 2012; 109: E2127–E2133.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wong KK, Engelman JA, Cantley LC . Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 2010; 20: 87–90.

    CAS  PubMed  Google Scholar 

  46. 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 USA 1999; 96: 4240–4245.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6: 117–127.

    CAS  PubMed  Google Scholar 

  48. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395–402.

    CAS  PubMed  Google Scholar 

  49. Esteva FJ, Guo H, Zhang S, Santa-Maria C, Stone S, Lanchbury JS et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 2010; 177: 1647–1656.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26.

    PubMed  PubMed Central  Google Scholar 

  51. Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PA, Xu R et al. FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J Clin Invest 2012; 122: 3211–3220.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cipriano R, Graham J, Miskimen KL, Bryson BL, Bruntz RC, Scott SA et al. FAM83B mediates EGFR- and RAS-driven oncogenic transformation. J Clin Invest 2012; 122: 3197–3210.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 2012; 149: 1098–1111.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Arkenau HT, Kefford R, Long GV . Targeting BRAF for patients with melanoma. Br J Cancer 2011; 104: 392–398.

    CAS  PubMed  Google Scholar 

  55. Lu CH, Wyszomierski SL, Tseng LM, Sun MH, Lan KH, Neal CL et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13: 5883–5888.

    CAS  PubMed  Google Scholar 

  56. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68: 9221–9230.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E et al. Only a subset of Met-activated pathways are required to sustain oncogene addiction. Sci Signal 2009; 2: ra80.

    PubMed  Google Scholar 

  58. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121: 179–193.

    CAS  PubMed  Google Scholar 

  59. Inoki K, Li Y, Zhu T, Wu J, Guan KL . TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 648–657.

    CAS  PubMed  Google Scholar 

  60. Laplante M, Sabatini DM . mTOR signaling at a glance. J Cell Sci 2009; 122: 3589–3594.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sabatini DM . mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6: 729–734.

    CAS  PubMed  Google Scholar 

  62. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 2010; 18: 39–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang Y, Ding Q, Yen CJ, Xia W, Izzo JG, Lang JY et al. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 2012; 21: 374–387.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 2007; 4: 1669–1679 discussion 1680.

    CAS  PubMed  Google Scholar 

  65. de La Motte Rouge T, Galluzzi L, Olaussen KA, Zermati Y, Tasdemir E, Robert T et al. A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res 2007; 67: 6253–6262.

    CAS  PubMed  Google Scholar 

  66. Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 2011; 1: 352–365.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ . Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10: 1201–1204.

    CAS  PubMed  Google Scholar 

  68. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 2008; 10: 138–148.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999; 96: 857–868.

    CAS  PubMed  Google Scholar 

  70. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ . Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 2003; 278: 18811–18816.

    CAS  PubMed  Google Scholar 

  71. Qi XJ, Wildey GM, Howe PH . Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem 2006; 281: 813–823.

    CAS  PubMed  Google Scholar 

  72. Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY et al. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol 2007; 27: 4006–4017.

    CAS  PubMed  Google Scholar 

  73. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–789.

    CAS  PubMed  Google Scholar 

  74. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 2005; 19: 159–170.

    CAS  PubMed  Google Scholar 

  75. Ding Q, Huo L, Yang JY, Xia W, Wei Y, Liao Y et al. Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res 2008; 68: 6109–6117.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF . The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 1999; 19: 6195–6206.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Booy EP, Henson ES, Gibson SB . Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 2011; 30: 2367–2378.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fan W, Tang Z, Yin L, Morrison B, Hafez-Khayyata S, Fu P et al. MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. Cancer Res 2011; 71: 4494–4505.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Catz SD, Johnson JL . Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 2001; 20: 7342–7351.

    CAS  PubMed  Google Scholar 

  80. Chen C, Edelstein LC, Gelinas C . The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 2000; 20: 2687–2695.

    PubMed  PubMed Central  Google Scholar 

  81. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9: 351–365.

    CAS  PubMed  Google Scholar 

  82. Lang JY, Hsu JL, Meric-Bernstam F, Chang CJ, Wang Q, Bao Y et al. BikDD eliminates breast cancer initiating cells and synergizes with lapatinib for breast cancer treatment. Cancer cell 2011; 20: 341–356.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Xie X, Xia W, Li Z, Kuo HP, Liu Y, Ding Q et al. Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models. Cancer cell 2007; 12: 52–65.

    CAS  PubMed  Google Scholar 

  84. Sher YP, Tzeng TF, Kan SF, Hsu J, Xie X, Han Z et al. Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival. Oncogene 2009; 28: 3286–3295.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li LY, Dai HY, Yeh FL, Kan SF, Lang J, Hsu JL et al. Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy. Oncogene 2011; 30: 1773–1783.

    CAS  PubMed  Google Scholar 

  86. Balint EE, Vousden KH . Activation and activities of the p53 tumour suppressor protein. Br J Cancer 2001; 85: 1813–1823.

    CAS  PubMed Central  Google Scholar 

  87. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC . HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001; 3: 973–982.

    CAS  PubMed  Google Scholar 

  88. Malmlof M, Roudier E, Hogberg J, Stenius U . MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 is activated in response to inhibited Akt signaling. J Biol Chem 2007; 282: 2288–2296.

    PubMed  Google Scholar 

  89. Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J . Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res 2004; 64: 2382–2389.

    CAS  PubMed  Google Scholar 

  90. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 2009; 15: 283–293.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10: 105–115.

    CAS  PubMed  Google Scholar 

  92. Ren Z, Schaefer TS . ErbB-2 activates Stat3 alpha in a Src- and JAK2-dependent manner. J Biol Chem 2002; 277: 38486–38493.

    CAS  PubMed  Google Scholar 

  93. Sen M, Joyce S, Panahandeh M, Li C, Thomas SM, Maxwell J et al. Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin Cancer Res 2012; 18: 4986–4996.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim SM, Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther 2012; 11: 2254–2264.

    CAS  PubMed  Google Scholar 

  95. Harada D, Takigawa N, Ochi N, Ninomiya T, Yasugi M, Kubo T et al. JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. Cancer Sci 2012; 103: 1795–1802.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Lo HW, Cao X, Zhu H, Ali-Osman F . Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to iressa and alkylators. Clin Cancer Res 2008; 14: 6042–6054.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 2011; 17: 461–469.

    PubMed  Google Scholar 

  98. Chiu HC, Chou DL, Huang CT, Lin WH, Lien TW, Yen KJ et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem Pharmacol 2011; 81: 1263–1270.

    CAS  PubMed  Google Scholar 

  99. Yamaguchi H, Hsu JL, Hung MC . Regulation of ubiquitination-mediated protein degradation by survival kinases in cancer. Front Oncol 2012; 2: 15.

    PubMed  PubMed Central  Google Scholar 

  100. Chen YJ, Wang YN, Chang WC . ERK2-mediated C-terminal serine phosphorylation of p300 is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. J Biol Chem 2007; 282: 27215–27228.

    CAS  PubMed  Google Scholar 

  101. Huang WC, Chen CC . Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. Mol Cell Biol 2005; 25: 6592–6602.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee DF, Hung MC . Advances in targeting IKK and IKK-related kinases for cancer therapy. Clin Cancer Res 2008; 14: 5656–5662.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Nickoloff BJ, Osborne BA, Miele L . Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene 2003; 22: 6598–6608.

    CAS  PubMed  Google Scholar 

  104. Kopan R, Ilagan MX . The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137: 216–233.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu ZJ, Xiao M, Balint K, Smalley KS, Brafford P, Qiu R et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res 2006; 66: 4182–4190.

    CAS  PubMed  Google Scholar 

  106. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203–1210.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Maraver A, Fernandez-Marcos PJ, Herranz D, Canamero M, Munoz-Martin M, Gomez-Lopez G et al. Therapeutic effect of gamma-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK. Cancer Cell 2012; 22: 222–234.

    CAS  PubMed  Google Scholar 

  108. Kolev V, Mandinova A, Guinea-Viniegra J, Hu B, Lefort K, Lambertini C et al. EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol 2008; 10: 902–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Osipo C, Patel P, Rizzo P, Clementz AG, Hao L, Golde TE et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 2008; 27: 5019–5032.

    CAS  PubMed  Google Scholar 

  110. Dong Y, Li A, Wang J, Weber JD, Michel LS . Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res 2010; 70: 5465–5474.

    CAS  PubMed  Google Scholar 

  111. Xie M, Zhang L, He CS, Xu F, Liu JL, Hu ZH et al. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J Cell Biochem 2012; 113: 1501–1513.

    CAS  PubMed  Google Scholar 

  112. Al-Hussaini H, Subramanyam D, Reedijk M, Sridhar SS . Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther 2011; 10: 9–15.

    CAS  PubMed  Google Scholar 

  113. Polakis P . The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17: 45–51.

    CAS  PubMed  Google Scholar 

  114. Logan CY, Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781–810.

    CAS  PubMed  Google Scholar 

  115. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509–1512.

    CAS  PubMed  Google Scholar 

  116. Tetsu O, McCormick F . Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.

    CAS  PubMed  Google Scholar 

  117. Jeong WJ, Yoon J, Park JC, Lee SH, Kaduwal S, Kim H et al. Ras stabilization through aberrant activation of Wnt/beta-catenin signaling promotes intestinal tumorigenesis. Sci Signal 2012; 5: ra30.

    PubMed  Google Scholar 

  118. Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S et al. Beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med 2012; 18: 892–901.

    CAS  PubMed  Google Scholar 

  119. Rasola A, Fassetta M, De Bacco F, D'Alessandro L, Gramaglia D, Di Renzo MF et al. A positive feedback loop between hepatocyte growth factor receptor and beta-catenin sustains colorectal cancer cell invasive growth. Oncogene 2007; 26: 1078–1087.

    CAS  PubMed  Google Scholar 

  120. Ji H, Wang J, Nika H, Hawke D, Keezer S, Ge Q et al. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-catenin from beta-catenin and transactivation of beta-catenin. Mol Cell 2009; 36: 547–559.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 2011; 480: 118–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Biechele TL, Kulikauskas RM, Toroni RA, Lucero OM, Swift RD, James RG et al. Wnt/beta-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci Signal 2012; 5: ra3.

    PubMed  PubMed Central  Google Scholar 

  123. Perkins ND . The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Cancer 2012; 12: 121–132.

    CAS  PubMed  Google Scholar 

  124. Perkins ND . Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 2007; 8: 49–62.

    CAS  PubMed  Google Scholar 

  125. Kanarek N, London N, Schueler-Furman O, Ben-Neriah Y . Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol 2010; 2: a000166.

    PubMed  PubMed Central  Google Scholar 

  126. Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 2011; 471: 523–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yang JY, Hung MC . A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin Cancer Res 2009; 15: 752–757.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Yang JY, Chang CJ, Xia W, Wang Y, Wong KK, Engelman JA et al. Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. Cancer Res 2010; 70: 4709–4718.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007; 130: 440–455.

    CAS  PubMed  Google Scholar 

  130. Yen CJ, Izzo JG, Lee DF, Guha S, Wei Y, Wu TT et al. Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett’s-associated esophageal adenocarcinoma. Cancer Res 2008; 68: 2632–2640.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 2004; 117: 225–237.

    CAS  PubMed  Google Scholar 

  132. Su JL, Cheng X, Yamaguchi H, Chang YW, Hou CF, Lee DF et al. FOXO3a-dependent mechanism of E1A-induced chemosensitization. Cancer Res 2011; 71: 6878–6887.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA et al. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Invest 2011; 121: 4685–4699.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Liu M, Lee DF, Chen CT, Yen CJ, Li LY, Lee HJ et al. IKKalpha activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell 2012; 45: 171–184.

    CAS  PubMed  Google Scholar 

  135. Carayol N, Wang CY . IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. Cell Signal 2006; 18: 1941–1946.

    CAS  PubMed  Google Scholar 

  136. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008; 105: 2070–2075.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 2009; 119: 3000–3010.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Suda K, Onozato R, Yatabe Y, Mitsudomi T . EGFR T790M mutation: a double role in lung cancer cell survival? J Thorac Oncol 2009; 4: 1–4.

    PubMed  Google Scholar 

  139. Sasaki T, Okuda K, Zheng W, Butrynski J, Capelletti M, Wang L et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010; 70: 10038–10043.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Shah NP, Sawyers CL . Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 2003; 22: 7389–7395.

    CAS  PubMed  Google Scholar 

  141. Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci USA 2010; 107: 15535–15540.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell 2012; 47: 570–584.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A et al. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 2012; 18: 74–82.

    CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the National Breast Cancer Foundation, Sister Institution Fund of China Medical University Hospital and MD Anderson Cancer Center, Patel Memorial Breast Cancer Research Fund, Center for Biological Pathways, and CCSG (CA16672).

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Yamaguchi, S-S Chang, J L Hsu & M-C Hung

  2. Graduate School of Biomedical Sciences, The University of Texas, Health Science Center at Houston, Houston, TX, USA

    S-S Chang & M-C Hung

  3. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan

    J L Hsu & M-C Hung

  4. Department of Biotechnology, Asia University, Taichung, Taiwan

    J L Hsu & M-C Hung

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  1. H Yamaguchi
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  2. S-S Chang
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Correspondence to M-C Hung.

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Yamaguchi, H., Chang, SS., Hsu, J. et al. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 33, 1073–1081 (2014). https://doi.org/10.1038/onc.2013.74

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