Advances in Targeting HER3 as an Anticancer Therapy

HER3 (ErbB3) is a unique member of the human epidermal growth factor receptor (EGFR) family (ErbB family). It functions only through dimerization with other members of the ErbB family and modulates activity and sensitivity to targeted cancer therapies. This paper briefly describes the mechanism of HER3 in signal transduction and its potential role in acquired resistance to EGFR- and HER2-targeted therapies. We also consider recent developments in HER3-targeting therapeutics and their combination with inhibitors of other ErbB members in clinical applications.

[1]  W. Gullick,et al.  Identification of c‐erbB‐3 binding sites for phosphatidylinositol 3′‐kinase and SHC using an EGF receptor/c‐erbB‐3 chimera. , 1994, The EMBO journal.

[2]  H. Esumi,et al.  Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. , 2002, Molecular biology of the cell.

[3]  H. Lane,et al.  ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors , 2005, Nature Reviews Cancer.

[4]  C. Moskaluk,et al.  Membranous expression of Her3 is associated with a decreased survival in head and neck squamous cell carcinoma , 2011, Journal of Translational Medicine.

[5]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[6]  Peter J. Wild,et al.  HER3 Is a Determinant for Poor Prognosis in Melanoma , 2008, Clinical Cancer Research.

[7]  A. C. Johannessen,et al.  Expression of c-erbB proto-oncogene family members in squamous cell carcinoma of the head and neck. , 1997, Anticancer research.

[8]  P. Jänne,et al.  Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab , 2011, Science Translational Medicine.

[9]  O. Larsson,et al.  Nuclear HER3 is associated with favorable overall survival in uveal melanoma , 2012, International journal of cancer.

[10]  N. Hellyer,et al.  ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. , 1998, The Biochemical journal.

[11]  Y. Yoshihama,et al.  Prognostic significance of ERRB3 overexpression in oral squamous cell carcinoma , 1995 .

[12]  V. Grantcharova,et al.  Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis , 2009, Science Signaling.

[13]  G. Helguera,et al.  IBC’s 22nd Annual Antibody Engineering and 9th Annual Antibody Therapeutics International Conferences and the 2011 Annual Meeting of The Antibody Society, December 5–8, 2011, San Diego, CA , 2011, mAbs.

[14]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[15]  D. Johnston,et al.  Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  C. Bokemeyer,et al.  Platinum-based chemotherapy plus cetuximab in head and neck cancer. , 2008, The New England journal of medicine.

[17]  M. Kraus,et al.  Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. , 1995, Oncogene.

[18]  M. Kraus,et al.  Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Ullrich,et al.  Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor , 1984, Nature.

[20]  R. Radhakrishnan,et al.  ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation , 2010, Proceedings of the National Academy of Sciences.

[21]  M. Heslin,et al.  Targeting ErbB3-mediated stromal–epithelial interactions in pancreatic ductal adenocarcinoma , 2011, British Journal of Cancer.

[22]  A. Ullrich,et al.  Toward the Prognostic Significance and Therapeutic Potential of HER3 Receptor Tyrosine Kinase in Human Colon Cancer , 2011, Clinical Cancer Research.

[23]  Y. Yatabe,et al.  Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. , 2008, Cancer research.

[24]  Ulrik B. Nielsen,et al.  Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3 , 2012, Molecular Cancer Therapeutics.

[25]  M. Sliwkowski,et al.  The influence of heregulins on human Schwann cell proliferation , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  C. Quinn,et al.  c‐erbB‐3 protein expression in human breast cancer: comparison with other tumour variables and survival , 1994, Histopathology.

[27]  H. Friess,et al.  Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. , 1998, Human pathology.

[28]  F. Ciardiello,et al.  Current status of targeted therapies in advanced gastric cancer , 2012, Expert opinion on therapeutic targets.

[29]  C. Arteaga.  HER3 and mutant EGFR meet MET , 2007, Nature Medicine.

[30]  A. Thomason,et al.  Transformation of NIH 3T3 Cells by HER3 or HER4 Receptors Requires the Presence of HER1 or HER2 (*) , 1996, The Journal of Biological Chemistry.

[31]  Andrew V Kossenkov,et al.  ErbB3 expression promotes tumorigenesis in pancreatic adenocarcinoma , 2010, Cancer biology & therapy.

[32]  D. Stern,et al.  Specificity within the EGF family/ErbB receptor family signaling network , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[33]  Monilola A. Olayioye,et al.  The ErbB signaling network: receptor heterodimerization in development and cancer , 2000, The EMBO journal.

[34]  T. Matsumura,et al.  Overexpression of c-erbB-3 in Various Stages of Human Squamous Cell Carcinomas , 1998, Oncology.

[35]  Jung Young Lee,et al.  ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas , 2006, International journal of cancer.

[36]  Gavin MacBeath,et al.  A quantitative protein interaction network for the ErbB receptors using protein microarrays , 2006, Nature.

[37]  M. Heslin,et al.  ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib , 2007, Cancer biology & therapy.

[38]  D. Barnes,et al.  Expression of the ERBB3 gene product in breast cancer. , 1992, British Journal of Cancer.

[39]  N. Leighl,et al.  Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line. , 2012, Current oncology.

[40]  L. Anderson,et al.  The ERBB3 receptor in cancer and cancer gene therapy , 2008, Cancer Gene Therapy.

[41]  Andre T Baron,et al.  Trastuzumab-induced HER reprogramming in "resistant" breast carcinoma cells. , 2009, Cancer research.

[42]  N. Hellyer,et al.  Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. , 1998, The Biochemical journal.

[43]  L. Cantley,et al.  ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor , 1994, Molecular and cellular biology.

[44]  J. Settleman,et al.  Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. , 2011, Cancer cell.

[45]  R. Coffey,et al.  Resistance to EGFR-targeted therapy: a family affair. , 2011, Cancer cell.

[46]  D. Salomon,et al.  Differential expression of epidermal growth factor-related proteins in human colorectal tumors. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Morris,et al.  Recent advances in novel targeted therapies for HER2-positive breast cancer , 2012, Anti-cancer drugs.

[48]  I. Ellis,et al.  C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. , 1996, British Journal of Cancer.

[49]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[50]  A. Ullrich,et al.  Insulin-like growth factor II precursor gene organization in relation to insulin gene family , 1984, Nature.

[51]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  P. Seeburg,et al.  Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells , 1984, Nature.

[53]  M. Kuwano,et al.  Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs , 2006, Clinical Cancer Research.

[54]  A. Ullrich,et al.  Heregulin‐dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. , 1995, The EMBO journal.

[55]  Na Zhang,et al.  Signaling via ErbB2 and ErbB3 Associates with Resistance and Epidermal Growth Factor Receptor (EGFR) Amplification with Sensitivity to EGFR Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cells , 2006, Clinical Cancer Research.

[56]  M. Lemmon,et al.  ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface , 2004, FEBS letters.

[57]  J. Contessa,et al.  Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation , 2005, Breast Cancer Research and Treatment.

[58]  P. Ghosh,et al.  Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. , 2011, Immunology, endocrine & metabolic agents in medicinal chemistry.

[59]  A. Psyrri,et al.  Prognostic significance of HER3 and HER4 protein expression in colorectal adenocarcinomas , 2006, BMC Cancer.

[60]  P. Seeburg,et al.  Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. , 1985, Science.

[61]  A. Ullrich,et al.  Chicken epidermal growth factor (EGF) receptor: cDNA cloning, expression in mouse cells, and differential binding of EGF and transforming growth factor alpha , 1988, Molecular and cellular biology.

[62]  M. Vincent,et al.  Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS , 2014, Front. Oncol..

[63]  K. Darcy,et al.  Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during Growth, Differentiation, and Apoptosis of Normal Rat Mammary Epithelial Cells , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[64]  G. Mills,et al.  Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors , 2003, Oncogene.

[65]  H. Wiley,et al.  The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling* , 1997, The Journal of Biological Chemistry.

[66]  K. Shokat,et al.  Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3 , 2007, Nature.

[67]  M. Somerfield,et al.  American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[69]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[70]  A. Papavassiliou,et al.  HER-3 in colorectal tumourigenesis: from mRNA levels through protein status to clinicopathologic relationships. , 2007, European journal of cancer.

[71]  M. Karamouzis,et al.  Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. , 2009, The Lancet. Oncology.

[72]  S. Nonogaki,et al.  Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  G. Plowman,et al.  Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[74]  D. Stern,et al.  ErbBs in mammary development. , 2003, Experimental cell research.

[75]  Xiaoming Deng,et al.  Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors. , 2003, Cancer research.

[76]  M. Kraus,et al.  Overexpression of erbB-2 or EGF receptor proteins present in early stage mammary carcinoma is detected simultaneously in matched primary tumors and regional metastases. , 1989, Oncogene.

[77]  D. Jonker,et al.  The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. , 2011, Discovery medicine.

[78]  P. W. Janes,et al.  Analysis of Grb7 Recruitment by Heregulin-activated erbB Receptors Reveals a Novel Target Selectivity for erbB3* , 1998, The Journal of Biological Chemistry.

[79]  D. Agus,et al.  HER kinase axis receptor dimer partner switching occurs in response to EGFR tyrosine kinase inhibition despite failure to block cellular proliferation. , 2010, Cancer research.

[80]  N. Bundred,et al.  Absence of HER4 Expression Predicts Recurrence of Ductal Carcinoma In situ of the Breast , 2005, Clinical Cancer Research.

[81]  A. Davies.  Neuronal survival: Early dependence on Schwann cells , 1998, Current Biology.

[82]  I. H. Koumakpayi,et al.  Expression and Nuclear Localization of ErbB3 in Prostate Cancer , 2006, Clinical Cancer Research.

[83]  H. Kim,et al.  Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. , 1997, The Biochemical journal.

[84]  S. Kamel‐Reid,et al.  Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. , 2012, Current oncology.

[85]  J. Koland,et al.  Mutation of a Shc Binding Site Tyrosine Residue in ErbB3/HER3 Blocks Heregulin-dependent Activation of Mitogen-activated Protein Kinase* , 1998, The Journal of Biological Chemistry.

[86]  M. Moasser,et al.  Targeting HER proteins in cancer therapy and the role of the non-target HER3 , 2007, British Journal of Cancer.

[87]  J. Baselga,et al.  Novel anticancer targets: revisiting ERBB2 and discovering ERBB3 , 2009, Nature Reviews Cancer.

[88]  Jennifer L Hunt,et al.  Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting , 2006, Clinical Cancer Research.

[89]  M. Sliwkowski,et al.  A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. , 2008, Cancer research.

[90]  A. Ullrich,et al.  Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences , 1984, Nature.

[91]  J. C. Lee,et al.  Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. , 2002, European journal of cancer.

[92]  Q. She,et al.  Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[93]  L. Anderson,et al.  Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549 , 2005, Oncogene.

[94]  Birgit Schoeberl,et al.  An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. , 2010, Cancer research.

[95]  Andrew D. Yates,et al.  Somatic mutations of the protein kinase gene family in human lung cancer. , 2005, Cancer research.

[96]  Kuala Lumpur Malaysia,et al.  Expression of c-erbB3 protein in primary breast carcinomas. , 1998, British Journal of Cancer.

[97]  T. Wurch,et al.  IBC's 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics International Conferences and 2010 Annual Meeting of The Antibody Society , 2011, mAbs.

[98]  J. Baselga,et al.  Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.