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HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

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Abstract

Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.

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References

  1. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012

  2. Berns K, Horlings HM, Hennessy BT et al (2007) A functional genetic approach identifies the PI3 K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402

    Article  CAS  PubMed  Google Scholar 

  3. Ross JS, Fletcher JA, Linette GP et al (2003) The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8:307–325

    Article  CAS  PubMed  Google Scholar 

  4. Cho HS, Mason K, Ramyar KX et al (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421:756–760

    Article  CAS  PubMed  Google Scholar 

  5. Riese DJ, Kim ED, Elenius K et al (1996) The epidermal growth factor receptor couples transforming growth factor-alpha, heparin-binding epidermal growth factor-like factor, and amphiregulin to Neu, ErbB-3, and ErbB-4. J Biol Chem 271:20047–20052

    Article  CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70

    Article  Google Scholar 

  7. Siegel PM, Muller WJ (1996) Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc Natl Acad Sci USA 93:8878–8883

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Graus-Porta D, Beerli RR, Daly JM, Hynes NE (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16:1647–1655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Stern DF, Kamps MP, Cao H (1988) Oncogenic activation of p185neu stimulates tyrosine phosphorylation in vivo. Mol Cell Biol 8:3969–3973

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Wulfkuhle JD, Berg D, Wolff C et al (2012) Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping. Clin Cancer Res 18:6426–6435

    Article  CAS  PubMed  Google Scholar 

  11. Holbro T, Beerli RR, Maurer F et al (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100:8933–8938

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Lipton A, Goodman L, Leitzel K et al (2013) HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat 141:43–53

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Garner AP, Bialucha CU, Sprague ER et al (2013) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 73:6024–6035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Phillips GD, Fields CT, Li G et al (2014) Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res 20:456–468

    Article  CAS  PubMed  Google Scholar 

  15. Sassen A, Rochon J, Wild P et al (2008) Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res 10:R2

    Article  PubMed Central  PubMed  Google Scholar 

  16. Nafi S, Generali D, Kramer-Marek G et al (2014) Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer. Oncotarget 2014

  17. Drebin JA, Link VC, Weinberg RA, Greene MI (1986) Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc Natl Acad Sci USA 83:9129–9133

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Baselga J, Norton L, Albanell J et al (1998) Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58:2825–2831

    CAS  PubMed  Google Scholar 

  19. Molina MA, Codony-Servat J, Albanell J et al (2001) Trastuzumab (Herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 61:4744–4749

    CAS  PubMed  Google Scholar 

  20. Le XF, Claret FX, Lammayot A et al (2003) The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J Biol Chem 278:23441–23450

    Article  CAS  PubMed  Google Scholar 

  21. Cuello M, Ettenberg SA, Clark AS et al (2001) Down-regulation of the erbB-2 receptor by trastuzumab (Herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res 61:4892–4900

    CAS  PubMed  Google Scholar 

  22. Collins DM, O’Donovan N, McGowan PM et al (2012) Trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in HER-2-non-amplified breast cancer cell lines. Ann Oncol 23:1788–1795

    Article  CAS  PubMed  Google Scholar 

  23. Gennari R, Menard S, Fagnoni F et al (2004) Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 10:5650–5655

    Article  CAS  PubMed  Google Scholar 

  24. Gril B, Palmieri D, Bronder JL et al (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100:1092–1103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nahta R, Yuan LX, Du Y, Esteva FJ (2007) Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther 6:667–674

    Article  CAS  PubMed  Google Scholar 

  26. Scaltriti M, Chandarlapaty S, Prudkin L et al (2010) Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res 16:2688–2695

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Xia W, Mullin RJ, Keith BR et al (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255–6263

    Article  CAS  PubMed  Google Scholar 

  28. Gilmer TM (2011) Lapatinib: functional genomics study leads to insights into mechanism of action. Mol Cancer Ther 10:2025

    Article  CAS  PubMed  Google Scholar 

  29. Lin NU, Dieras V, Paul D et al (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459

    Article  CAS  PubMed  Google Scholar 

  30. Xia W, Gerard CM, Liu L et al (2005) Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24:6213–6221

    Article  CAS  PubMed  Google Scholar 

  31. Scaltriti M, Verma C, Guzman M et al (2009) Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 28:803–814

    Article  CAS  PubMed  Google Scholar 

  32. Blackwell KL, Burstein HJ, Storniolo AM et al (2012) Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 30:2585–2592

    Article  CAS  PubMed  Google Scholar 

  33. Piccart-Gebhart MJHA, Baselga J et al (2014) First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). JCO 32:5s

    Article  Google Scholar 

  34. Gelmon KA Boyle F, Kaufman B, et al (2012) Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919. JCO 30

  35. Agus DB, Akita RW, Fox WD et al (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127–137

    Article  CAS  PubMed  Google Scholar 

  36. Lee-Hoeflich ST, Crocker L, Yao E et al (2008) A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68:5878–5887

    Article  CAS  PubMed  Google Scholar 

  37. Scheuer W, Friess T, Burtscher H et al (2009) Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 69:9330–9336

    Article  CAS  PubMed  Google Scholar 

  38. Cassady JM, Chan KK, Floss HG, Leistner E (2004) Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52:1–26

    Article  CAS  Google Scholar 

  39. Erickson HK, Park PU, Widdison WC et al (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433

    Article  CAS  PubMed  Google Scholar 

  40. Junttila TT, Li G, Parsons K et al (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 128:347–356

    Article  CAS  PubMed  Google Scholar 

  41. Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791

    Article  CAS  PubMed  Google Scholar 

  42. Bianchini G, Gianni L (2014) The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 15:e58–e68

    Article  CAS  PubMed  Google Scholar 

  43. Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47

    Article  CAS  PubMed  Google Scholar 

  44. Loi SMS, Lambrechts D (2012) Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival in early breast cancer (BC):results from the FinHER trial. Proc Am Soc Clin Oncol 30:282–290

    Article  Google Scholar 

  45. Loi S, Michiel S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Brown DN, Kellokumpu-Lehtinen P-L, Bono P, Kataja V, Desmedt C, Piccart-Gebhart MJ, Loibl S, Untch M, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2013) Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). Cancer Res 73: Abstr S1-05

  46. Loi S, Sirtaine N, Piette F et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860–867

    Article  CAS  PubMed  Google Scholar 

  47. Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160

    Article  CAS  PubMed  Google Scholar 

  48. Junttila TT, Parsons K, Olsson C et al (2010) Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer. Cancer Res 70:4481–4489

    Article  CAS  PubMed  Google Scholar 

  49. Fan X, Brezski RJ, Fa M et al (2012) A single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy. Breast Cancer Res 14:R116

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Kinder M, Greenplate AR, Grugan KD et al (2013) Engineered protease-resistant antibodies with selectable cell-killing functions. J Biol Chem 288:30843–30854

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Stagg J, Loi S, Divisekera U et al (2011) Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci USA 108:7142–7147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Park S, Jiang Z, Mortenson ED et al (2010) The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18:160–170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Kohrt HE, Houot R, Goldstein MJ et al (2011) CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 117:2423–2432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Kohrt HE, Houot R, Weiskopf K et al (2012) Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 122:1066–1075

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Stagg J, Loi S, Divisekera U et al (2011) Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci USA 108:7142–7147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Park S, Jiang Z, Mortenson ED et al (2010) The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18:160–170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Wang B, Wang Q, Wang Z et al (2014) Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res 74:5746–5757

    Article  CAS  PubMed  Google Scholar 

  58. Tagliabue E, Sfondrini L, Regondi V et al (2012) Chemotherapy can enhance trastuzumab-mediated ADCC. Cancer Res 72: P5-18-10

  59. Disis ML, Calenoff E, McLaughlin G et al (1994) Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54:16–20

    CAS  PubMed  Google Scholar 

  60. Peoples GE, Goedegebuure PS, Smith PS et al (1995) Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 92:432436

    Google Scholar 

  61. Salazar L, Goodell V, O’Meara M et al (2009) Persistent immunity and survival after immunization with a HER2/neu (HER2) vaccine. J Clin Oncol 27:15s (suppl; abstr. 3010)

  62. Mittendorf EA, Clifton GT, Holmes JP et al (2012) Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 118:2594–2602

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Holmes JP, Gates JD, Benavides LC et al (2008) Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 113:1666–1675

    Article  CAS  PubMed  Google Scholar 

  64. Disis ML, Schiffman K, Guthrie K et al (2004) Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein–based vaccine. J Clin Oncol 22:1916–1925

    Article  CAS  PubMed  Google Scholar 

  65. Limentani S, Dorval T, White S et al (2005) Phase I dose-escalation trial of a recombinant HER2 vaccine in patients with Stage II/III HER2+ breast cancer. J Clin Oncol 23:16s (suppl; abstr. 2520)

  66. Emens LA, Asquith JM, Leatherman JM et al (2009) Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol 27:5911–5918

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Milani A, Sangiolo D, Montemurro F et al (2013) Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol 24:1740–1748

    Article  CAS  PubMed  Google Scholar 

  69. Nagy P, Friedlander E, Tanner M et al (2005) Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res 65:473–482

    CAS  PubMed  Google Scholar 

  70. Esteva FJ, Guo H, Zhang S et al (2010) PTEN, PIK3CA, p-AKT, and p-p70S6 K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177:1647–1656

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Browne BC, Eustace AJ, Kennedy S et al (2012) Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours. Breast Cancer Res Treat 136:717–727

    Article  CAS  PubMed  Google Scholar 

  72. Zhang S, Huang WC, Li P et al (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 17:461–469

    Article  PubMed  Google Scholar 

  73. Saez R, Molina MA, Ramsey EE et al (2006) p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res 12:424–431

    Article  CAS  PubMed  Google Scholar 

  74. Guarneri V, Frassoldati A, Bottini A et al (2012) Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol 30:1989–1995

    Article  CAS  PubMed  Google Scholar 

  75. Gayle SSAS, O’Regan RM, Nahta R (2012) Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anti-Cancer Agents Med Chem 12:151–162

    Article  CAS  Google Scholar 

  76. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Zardavas D FD, Borwn DM, et al (2013) Abstract P2-11-02: Understanding the biology and prognosis of PIK3CA gene mutations in primary breast cancer using gene expression profiling: A pooled analysis. Cancer Res 73

  78. Loi S, Michiels S, Lambrechts D et al (2013) Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst 105:960–967

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Hennessy BT, Smith DL, Ram PT et al (2005) Exploiting the PI3 K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004

    Article  CAS  PubMed  Google Scholar 

  80. S Loibl CD, A Schneeweis, et al (2013) Abstract S4-06: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. Cancer Res 73

  81. Garcia-Garcia C, Ibrahim YH, Serra V et al (2012) Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 18:2603–2612

    Article  CAS  PubMed  Google Scholar 

  82. Andre F, O’Regan R, Ozguroglu M et al (2014) Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15:580–591

    Article  CAS  PubMed  Google Scholar 

  83. Sun SY, Rosenberg LM, Wang X et al (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65:7052–7058

    Article  CAS  PubMed  Google Scholar 

  84. Serra V, Markman B, Scaltriti M et al (2008) NVP-BEZ235, a dual PI3 K/mTOR inhibitor, prevents PI3 K signaling and inhibits the growth of cancer cells with activating PI3 K mutations. Cancer Res 68:8022–8030

    Article  CAS  PubMed  Google Scholar 

  85. Liu N, Rowley BR, Bull CO et al (2013) BAY 80-6946 is a highly selective intravenous PI3 K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft models. Mol Cancer Ther 12:2319–2330

    Article  CAS  PubMed  Google Scholar 

  86. Dreyling M, Morschhauser F, Bron D, Bouabdallah K, Vitolo U, Linton K, Van Den Neste E, Mappa S, Giurescu M, Childs BH, Zinzani PL (2013) Preliminary results of a Phase II study of single agent bay 80-6946, a novel PI3 K inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma. Blood 122:87

    Google Scholar 

  87. Junttila TT, Akita RW, Parsons K et al (2009) Ligand-independent HER2/HER3/PI3 K complex is disrupted by trastuzumab and is effectively inhibited by the PI3 K inhibitor GDC-0941. Cancer Cell 15:429–440

    Article  CAS  PubMed  Google Scholar 

  88. Saura C, Bendell J, Jerusalem G et al (2014) Phase Ib study of buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on trastuzumab-based therapy. Clin Cancer Res 20:1935–1945

    Article  CAS  PubMed  Google Scholar 

  89. Rabindran SK, Discafani CM, Rosfjord EC et al (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958–3965

    Article  CAS  PubMed  Google Scholar 

  90. Canonici A, Gijsen M, Mullooly M et al (2013) Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget 4:1592–1605

    PubMed Central  PubMed  Google Scholar 

  91. Awada A, Dirix L, Manso Sanchez L et al (2013) Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol 24:109–116

    Article  CAS  PubMed  Google Scholar 

  92. Bose R, Kavuri SM, Searleman AC et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Li D, Ambrogio L, Shimamura T et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Lin NU, Winer EP, Wheatley D et al (2012) A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 133:1057–1065

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Schuler M, Awada A, Harter P et al (2012) A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 134:1149–1159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Rimawi MF, Aleixo S, Rozas AA, et al (2012) A neoadjuvant, randomized, open-label phase II trial of afatinib (A) versus trastuzumab (T) versus lapatinib (L) in patients (pts) with locally advanced HER2-positive breast cancer (BC). JCO 30

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Acknowledgment

This work was supported by the Irish Cancer Society (CRS11ELS), the Health Research Board (HRA/POR2012/054), RCSI Seed Funding 2014 and Molecular Therapeutics for Cancer Ireland (08-SRC-B1410).The authors have no financial disclosures.

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Authors and Affiliations

  1. Department of Medical Oncology, Molecular Medicine Laboratories, ERC Smurift Building, Royal College of Surgeons in Ireland, Dublin, Ireland

    N. Elster, S. Toomey, A. J. Eustace & B. T. Hennessy

  2. National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland

    D. M. Collins & J. Crown

  3. Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland

    J. Crown

  4. Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland

    B. T. Hennessy

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  1. N. Elster
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  2. D. M. Collins
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  5. A. J. Eustace
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  6. B. T. Hennessy
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Correspondence to B. T. Hennessy.

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Eustace AJ and Hennessy BT Joint senior authors have contributed equally to this work.

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Elster, N., Collins, D.M., Toomey, S. et al. HER2-family signalling mechanisms, clinical implications and targeting in breast cancer. Breast Cancer Res Treat 149, 5–15 (2015). https://doi.org/10.1007/s10549-014-3250-x

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