2,949
Views
35
CrossRef citations to date
0
Altmetric
Reviews

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

, &
Pages 576-592 | Received 14 May 2015, Accepted 26 Sep 2015, Published online: 18 Nov 2015

References

  • Stewart BW, Wild CP. World cancer report 2014. Lyon, France: IARC, WHO Press; 2014
  • Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiology (Bethesda) 2010; 25:85-101; PMID:20430953
  • Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene 2000; 19:5548-57; PMID:11114734
  • Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012; 12:553-63; PMID:22785351
  • Roskoski R, Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 2014; 79:34-74; PMID:24269963
  • Cohen S, Fava RA, Sawyer ST. Purification and characterization of epidermal growth factor receptor/protein kinase from normal mouse liver. Proc Natl Acad Sci USA 1982; 79:6237-41
  • Lax I, Burgess WH, Bellot F, Ullrich A, Schlessinger J, Givol D. Localization of a major receptor-binding domain for epidermal growth factor by affinity labeling. Mol Cell Biol 1988; 8:1831-4; PMID:3260004
  • Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003; 12:541-52; PMID:14527402
  • Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 1996; 16:5276-87; PMID:8816440
  • Burgess AW. EGFR family: structure physiology signalling and therapeutic targets. Growth Factors 2008; 26:263-74; PMID:18800267
  • Clayton AH, Walker F, Orchard SG, Henderson C, Fuchs D, Rothacker J, Nice EC, Burgess AW. Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor-A multidimensional microscopy analysis. J Biol Chem 2005; 280:30392-9; PMID:15994331
  • Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA, et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 2002; 110:763-73; PMID:12297049
  • Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37; PMID:11252954
  • Barros FF, Powe DG, Ellis IO, Green AR. Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments. Histopathol 2010; 56:560-72
  • Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem 2006; 75:93-109; PMID:16756486
  • 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 Eng J Med 2004; 350:2129-39
  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497-500; PMID:15118125
  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004; 101:13306-11; PMID:15329413; http://dx.doi.org/10.1073/pnas.0405220101
  • Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 2005; 10:461-6; PMID:16079312; http://dx.doi.org/10.1634/theoncologist.10-7-461
  • Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004; 64:6652-9; PMID:15374980; http://dx.doi.org/10.1158/0008-5472.CAN-04-1168
  • 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; http://dx.doi.org/10.1038/nrclinonc.2011.177
  • Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Therapeutics 2012; 343:342-50; http://dx.doi.org/10.1124/jpet.112.197756
  • Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327-34; PMID:23816960; http://dx.doi.org/10.1200/JCO.2012.44.2806
  • Janne PA, Ramalingam SS, Yang JC-H, Ahn MJ, Kim DW, Kim SW, Planchard D, Ohe Y, Felip E, Watkins C, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2014; 32:8009
  • Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Eng J med 2015; 372:1700-9; http://dx.doi.org/10.1056/NEJMoa1413654
  • Kim DW, Lee DH, Kang JH, Park K, Han JY, Lee JS, Jang IJ, Kim HY, Son J, Kim JH. Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs). ASCO Meeting Abstracts 2014; 32:8011
  • Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983; 1:511-29; PMID:6094961
  • Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst 1988; 80:1605-11; PMID:3193478; http://dx.doi.org/10.1093/jnci/80.20.1605
  • Prewett M, Rockwell P, Rockwell RF, Giorgio NA, Mendelsohn J, Scher HI, Goldstein NI. The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother Emphasis Tumor Immunol 1996; 19:419-27; PMID:9041461; http://dx.doi.org/10.1097/00002371-199611000-00006
  • 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 Eng J Med 2004; 351:337-45; http://dx.doi.org/10.1056/NEJMoa033025
  • Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 2012; 18:221-3; PMID:22270724; http://dx.doi.org/10.1038/nm.2609
  • Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26:1626-34; PMID:18316791; http://dx.doi.org/10.1200/JCO.2007.14.7116
  • Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66:3992-5; PMID:16618717; http://dx.doi.org/10.1158/0008-5472.CAN-06-0191
  • Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Eng J Med 2013; 369:1023-34; http://dx.doi.org/10.1056/NEJMoa1305275
  • Bokemeyer C, Kohne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, Beier F, Duecker K, van Krieken JH, Tejpar S. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer 2015; 51:1243-52; PMID:25937522; http://dx.doi.org/10.1016/j.ejca.2015.04.007
  • Bertotti A, Sassi F. Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies. Clin Cancer Res 2015; 21:3377-83; PMID:26071484; http://dx.doi.org/10.1158/1078-0432.CCR-14-0848
  • Ciardiello F, Normanno N, Martinelli E, Troiani T, Cardone C, Nappi A, Rachiglio AM, Lambiase M, Pisconti S, Giuliani F, et al. LBA-09 • Cetuximab beyond progression in RAS wild type (WT) metastatic colorectal cancer (mCRC): the CAPRI-GOIM randomized phase II study of FOLFOX versus FOLFOX plus cetuximab. Ann Oncol 2015; 26:iv120-iv1; http://dx.doi.org/10.1093/annonc/mdv262.09
  • Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 1985; 41:697-706; PMID:2860972; http://dx.doi.org/10.1016/S0092-8674(85)80050-7
  • Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell biol 1989; 9:1165-72; PMID:2566907; http://dx.doi.org/10.1128/MCB.9.3.1165
  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992; 89:4285-9; PMID:1350088; http://dx.doi.org/10.1073/pnas.89.10.4285
  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med 2001; 344:783-92; http://dx.doi.org/10.1056/NEJM200103153441101
  • Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer cell 2002; 2:127-37; PMID:12204533; http://dx.doi.org/10.1016/S1535-6108(02)00097-1
  • Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010; 10:489-91; PMID:21147694; http://dx.doi.org/10.3816/CBC.2010.n.065
  • Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013; 14:461-71; PMID:23602601; http://dx.doi.org/10.1016/S1470-2045(13)70130-X
  • Cortes J, Roche H. Docetaxel combined with targeted therapies in metastatic breast cancer. Cancer Treatment Rev 2012; 38:387-96; http://dx.doi.org/10.1016/j.ctrv.2011.08.001
  • Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010; 28:2698-704; PMID:20421541; http://dx.doi.org/10.1200/JCO.2009.26.2071
  • Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, Guardino E, Lu M, Zheng M, Girish S, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30:3234-41; PMID:22649126; http://dx.doi.org/10.1200/JCO.2011.40.5902
  • Plowman GD, Whitney GS, Neubauer MG, Green JM, McDonald VL, Todaro GJ, Shoyab M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci USA 1990; 87:4905-9; PMID:2164210; http://dx.doi.org/10.1073/pnas.87.13.4905
  • Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA. 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. Proc Natl Acad Sci USA 1989; 86:9193-7; PMID:2687875; http://dx.doi.org/10.1073/pnas.86.23.9193
  • Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci USA 2010; 107:7692-7; PMID:20351256; http://dx.doi.org/10.1073/pnas.1002753107
  • Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 1995; 14:4267-75; PMID:7556068
  • Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996; 15:2452-67; PMID:8665853
  • Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, 3rd, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 2003; 100:8933-8; PMID:12853564; http://dx.doi.org/10.1073/pnas.1537685100
  • Steinkamp MP, Low-Nam ST, Yang S, Lidke KA, Lidke DS, Wilson BS. erbB3 is an active tyrosine kinase capable of homo- and heterointeractions. Mol Cell Biol 2014; 34:965-77; PMID:24379439; http://dx.doi.org/10.1128/MCB.01605-13
  • Waterman H, Sabanai I, Geiger B, Yarden Y. Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 1998; 273:13819-27; PMID:9593726; http://dx.doi.org/10.1074/jbc.273.22.13819
  • Sak MM, Breen K, Ronning SB, Pedersen NM, Bertelsen V, Stang E, Madshus IH. The oncoprotein ErbB3 is endocytosed in the absence of added ligand in a clathrin-dependent manner. Carcinogenesis 2012; 33:1031-9; PMID:22436610; http://dx.doi.org/10.1093/carcin/bgs128
  • Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011; 19:58-71; PMID:21215704; http://dx.doi.org/10.1016/j.ccr.2010.10.031
  • Huang Z, Choi BK, Mujoo K, Fan X, Fa M, Mukherjee S, Owiti N, Zhang N, An Z. The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling. Oncogene 2014; 34(9):1105-15; PMID:24662824; http://dx.doi.org/10.1038/onc.2014.56
  • Cao Z, Wu X, Yen L, Sweeney C, Carraway KL, 3rd. Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1. Mol Cell Biol 2007; 27:2180-8; PMID:17210635; http://dx.doi.org/10.1128/MCB.01245-06
  • Zhao Z, Li R, Sha S, Wang Q, Mao W, Liu T. Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation. Cancer Biol Therapy 2014; 15:1404-12; http://dx.doi.org/10.4161/cbt.29923
  • Yu J, Li Q, Xu Q, Liu L, Jiang B. MiR-148a inhibits angiogenesis by targeting ERBB3. J Biomed Res 2011; 25:170-7; PMID:23554686; http://dx.doi.org/10.1016/S1674-8301(11)60022-5
  • Yan X, Chen X, Liang H, Deng T, Chen W, Zhang S, Liu M, Gao X, Liu Y, Zhao C, et al. miR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer. Mol Cancer 2014; 13:220; PMID:25248370; http://dx.doi.org/10.1186/1476-4598-13-220
  • Wang S, Huang J, Lyu H, Lee CK, Tan J, Wang J, Liu B. Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death Dis 2013; 4:e556; PMID:23519125; http://dx.doi.org/10.1038/cddis.2013.79
  • Mujoo K, Choi BK, Huang Z, Zhang N, An Z. Regulation of ERBB3/HER3 signaling in cancer. Oncotarget 2014; 5:10222-36; PMID:25400118; http://dx.doi.org/10.18632/oncotarget.2655
  • Ma J, Lyu H, Huang J, Liu B. Targeting of erbB3 receptor to overcome resistance in cancer treatment. Mol Cancer 2014; 13:105; PMID:24886126; http://dx.doi.org/10.1186/1476-4598-13-105
  • Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 2013; 23:603-17; PMID:23680147; http://dx.doi.org/10.1016/j.ccr.2013.04.012
  • Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R. Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer J Int Du Cancer 2003; 106:758-65; http://dx.doi.org/10.1002/ijc.11273
  • Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E, Prigent SA, Gullick WJ, Hurst HC. Expression of the ERBB3 gene product in breast cancer. Br J Cancer 1992; 66:1116-21; PMID:1333787; http://dx.doi.org/10.1038/bjc.1992.420
  • Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst 2013; 105:266-73; PMID:23221996; http://dx.doi.org/10.1093/jnci/djs501
  • Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2008; 14:2895-9; PMID:18483355; http://dx.doi.org/10.1158/1078-0432.CCR-07-2248
  • Engelman JA, Settleman J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 2008; 18:73-9; PMID:18325754; http://dx.doi.org/10.1016/j.gde.2008.01.004
  • Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res 2009; 69:2191-4; PMID:19276389; http://dx.doi.org/10.1158/0008-5472.CAN-08-1056
  • Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, Dave B, Cook RS, Pao W, McKinely E, et al. Transcriptional and posttranslational upregulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci USA 2011; 108:5021-6; PMID:21385943; http://dx.doi.org/10.1073/pnas.1016140108
  • Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007; 445:437-41; PMID:17206155; http://dx.doi.org/10.1038/nature05474
  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316:1039-43; PMID:17463250; http://dx.doi.org/10.1126/science.1141478
  • Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PM. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 2008; 27:3944-56; PMID:18297114; http://dx.doi.org/10.1038/onc.2008.19
  • Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, Fartoux L, Venot C, Bladt F, Housset C, Rosmorduc O. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 2009; 15:5445-56; PMID:19706799; http://dx.doi.org/10.1158/1078-0432.CCR-08-2980
  • Wang S, Huang X, Lee CK, Liu B. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 2010; 29:4225-36; PMID:20498641; http://dx.doi.org/10.1038/onc.2010.180
  • Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG, Bartlett JM. Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clin Cancer Res 2005; 11:4835-42; PMID:16000581; http://dx.doi.org/10.1158/1078-0432.CCR-05-0196
  • Schulze WX, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Sys Biol 2005; 1:2005 0008
  • Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994; 13:2831-41; PMID:8026468
  • Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML, et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 2008; 26:1066-72; PMID:18212337; http://dx.doi.org/10.1200/JCO.2007.13.9949
  • Xia W, Petricoin EF, 3rd, Zhao S, Liu L, Osada T, Cheng Q, Wulfkuhle JD, Gwin WR, Yang X, Gallagher RI, et al. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res 2013; 15:R85; PMID:24044505; http://dx.doi.org/10.1186/bcr3480
  • Pierobon M, Wulfkuhle J, Liotta L, Petricoin E. Application of molecular technologies for phosphoproteomic analysis of clinical samples. Oncogene 2015; 34:805-14; PMID:24608425; http://dx.doi.org/10.1038/onc.2014.16
  • Wulfkuhle JD, Berg D, Wolff C, Langer R, Tran K, Illi J, Espina V, Pierobon M, Deng J, DeMichele A, et al. Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping. Clin Cancer Res 2012; 18:6426-35; PMID:23045247; http://dx.doi.org/10.1158/1078-0432.CCR-12-0452
  • Mancini M, Gaborit N, Lindzen M, Salame TM, Dall'Ora M, Sevilla-Sharon M, Abdul-Hai A, Downward J, Yarden Y. Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. Sci Signal 2015; 8:ra53; PMID:26038598
  • Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK, Lupu R. Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 2003; 22:761-8; PMID:12569369; http://dx.doi.org/10.1038/sj.onc.1206130
  • Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, Ross S, Goldenberg D, Merchant M, Tien J, et al. Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer. Sci Trans Med 2013; 5:171ra18; http://dx.doi.org/10.1126/scitranslmed.3004438
  • Lindzen M, Carvalho S, Starr A, Ben-Chetrit N, Pradeep CR, Kostler WJ, Rabinkov A, Lavi S, Bacus SS, Yarden Y. A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis. Oncogene 2012; 31:3505-15; PMID:22105361; http://dx.doi.org/10.1038/onc.2011.518
  • Jay SM, Kurtagic E, Alvarez LM, de Picciotto S, Sanchez E, Hawkins JF, Prince RN, Guerrero Y, Treasure CL, Lee RT, et al. Engineered bivalent ligands to bias ErbB receptor-mediated signaling and phenotypes. J Biol Chem 2011; 286:27729-40; PMID:21622572; http://dx.doi.org/10.1074/jbc.M111.221093
  • Hickinson DM, Klinowska T, Speake G, Vincent J, Trigwell C, Anderton J, Beck S, Marshall G, Davenport S, Callis R, et al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. Clin Cancer Res 2010; 16:1159-69; PMID:20145185; http://dx.doi.org/10.1158/1078-0432.CCR-09-2353
  • Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Seminars Oncol 2001; 28:80-5; http://dx.doi.org/10.1016/S0093-7754(01)90285-4
  • Rixe O, Franco SX, Yardley DA, Johnston SR, Martin M, Arun BK, Letrent SP, Rugo HS. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2009; 64:1139-48; PMID:19294387; http://dx.doi.org/10.1007/s00280-009-0975-z
  • Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL. The Potential of panHER Inhibition in Cancer. Front Oncol 2015; 5:2; PMID:25674538; http://dx.doi.org/10.3389/fonc.2015.00002
  • Wu Y, Zhang Y, Wang M, Li Q, Qu Z, Shi V, Kraft P, Kim S, Gao Y, Pak J, et al. Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models. Mol Cancer Therapeutics 2013; 12:427-37; http://dx.doi.org/10.1158/1535-7163.MCT-12-0838
  • Citri A, Gan J, Mosesson Y, Vereb G, Szollosi J, Yarden Y. Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation. EMBO Rep 2004; 5:1165-70; PMID:15568014; http://dx.doi.org/10.1038/sj.embor.7400300
  • Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D'Andrea G, Dickler M, Moynahan ME, Sugarman S, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011; 17:5132-9; PMID:21558407; http://dx.doi.org/10.1158/1078-0432.CCR-11-0072
  • Chen CH, Chernis GA, Hoang VQ, Landgraf R. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci USA 2003; 100:9226-31; PMID:12874383; http://dx.doi.org/10.1073/pnas.1332660100
  • Kanthala S, Banappagari S, Gokhale A, Liu YY, Xin G, Zhao Y, Jois S. Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer. Chem Biol Drug Design 2014; 85(6):702-14; http://dx.doi.org/10.1111/cbdd.12453
  • Ren XR, Wang J, Osada T, Mook RA, Jr., Morse MA, Barak LS, Lyerly HK, Chen W. Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth. Breast Cancer Res 2015; 17:528; http://dx.doi.org/10.1186/s13058-015-0528-9
  • Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben-Baruch N, Leitner O, Ratzkin BJ, Bacus SS, Yarden Y. An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB-3 and ErbB-4. J Biol Chem 1996; 271:7620-9; PMID:8631797; http://dx.doi.org/10.1074/jbc.271.13.7620
  • Freeman D, Ogbagabriel S, Rothe M, Radinsky R, Treder M. Abstract LB-21: Fully human Anti-HER3 monoclonal antibodies (mAbs) have unique in vitro and in vivo functional and antitumor activities versus other HER family inhibitors. Proc 99th AACR Annual Meeting. Cancer Res 2008; 68:LB-21
  • Treder M, Hartmann S, Ogbagabriel S, Borges E, Green L, Kang J, Radinsky R, Rothe M, Freeman D. Abstract LB-20: Fully human Anti-HER3 monoclonal antibodies (mAbs) inhibit oncogenic signaling and tumor cell growth in vitro and in vivo. Proceedings of the 99th AACR Annual Meeting. Cancer Res 2008; 68:LB-20
  • Freeman DJ, Ogbagabriel S, Bready J, Sun J-R, Radinsky R, Hettmann T. Abstract A182: U3–1287 (AMG 888), a fully human anti-HER3 mAb, demonstrates in vitro and in vivo efficacy in the FaDu model of human squamous cell carcinoma of the head and neck (SCCHN). AACR-NCI-EORTC Int Conf Mol Targets Cancer Therapeutics. Mol Cancer Ther 2011; 10:A182; http://dx.doi.org/10.1158/1535-7163.TARG-11-A182
  • LoRusso P, Janne PA, Oliveira M, Rizvi N, Malburg L, Keedy V, Yee L, Copigneaux C, Hettmann T, Wu CY, et al. Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 2013; 19:3078-87; PMID:23591447; http://dx.doi.org/10.1158/1078-0432.CCR-12-3051
  • Li C, Brand TM, Iida M, Huang S, Armstrong EA, van der Kogel A, Wheeler DL. Human epidermal growth factor receptor 3 (HER3) blockade with U3-1287/AMG888 enhances the efficacy of radiation therapy in lung and head and neck carcinoma. Discov Med 2013; 16:79-92; PMID:23998444
  • Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, Sakamoto H, Kitano M, Tamura T, Nishio K, et al. The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget 2014; 5:11847-56; PMID:25474137; http://dx.doi.org/10.18632/oncotarget.2663
  • Von Pawel J, Tseng J, Dediu M, Schumann C, Moritz B, Mendell-Harary J, Jin X, Feng W, Copigneaux C, Beckman RA. Abstract 8045: Phase 2 HERALD study of patritumab (P) with erlotinib (E) in advanced NSCLC subjects (SBJs). J Clin Oncol - 2014 ASCO Annual Meeting 2014; 32:5s
  • Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 2010; 70:2485-94; PMID:20215504; http://dx.doi.org/10.1158/0008-5472.CAN-09-3145
  • Schoeberl B, Pace EA, Fitzgerald JB, Harms BD, Xu L, Nie L, Linggi B, Kalra A, Paragas V, Bukhalid R, et al. Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal 2009; 2:ra31; PMID:19567914; http://dx.doi.org/10.1126/scisignal.2000352
  • Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A, et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer cell 2010; 17:298-310; PMID:20227043; http://dx.doi.org/10.1016/j.ccr.2009.12.047
  • Liles JS, Arnoletti JP, Kossenkov AV, Mikhaylina A, Frost AR, Kulesza P, Heslin MJ, Frolov A. Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma. Br J Cancer 2011; 105:523-33; PMID:21792199; http://dx.doi.org/10.1038/bjc.2011.263
  • Curley M, Kalra A, Fulgham A, Xiao D, Allen J, Wainszelbaum M, Garcia G, Kubasek W, MacBeath G. Abstract 141: MM-121, an Anti-ErbB3 antibody, Inhibits PI3K/AKT Signaling and Viability in platinum-resistant Ovarian Cells and in Primary Ascites Derived From Chemo-resistant Ovarian Cancer Patients. Proc 24 EORTC – NCI – AACR Symposium Mol Targets Cancer Therapeutics 2012; 48 (6 suppl):43-4
  • Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, Liu B. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer 2013; 12:134; PMID:24215614; http://dx.doi.org/10.1186/1476-4598-12-134
  • Henry C, Geslin C, Blanchet AM, Nicolazzi C, Garcia G, Vincent L, Blanc V, Tabah-Fisch I, Chiron M. Abstract 325: MM-121 (SAR256212), an Anti-ErbB3 Monoclonal Antibody, Shows Synergistic Tumor Growth Inhibition in Combination with a Pan-PI3K Inhibitor or a Microtubule Inhibitor Through ErbB3 Expression Modulation. Proc 24 EORTC – NCI – AACR Symposium Mol Targets Cancer Therapeutics 2012; 48:99
  • Curley MD, Sabnis GJ, Wille L, Adiwijaya BS, Garcia G, Moyo V, Kazi AA, Brodie A, MacBeath G. Seribantumab, an anti-ERBB3 antibody, delays the onset of resistance and restores sensitivity to letrozole in an estrogen receptor-positive breast cancer model. Mol Cancer Therapeutics 2015
  • Jiang N, Wang D, Hu Z, Shin HJ, Qian G, Rahman MA, Zhang H, Amin AR, Nannapaneni S, Wang X, et al. Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma. Mol Cancer Therapeutics 2014; 13:1826-36; http://dx.doi.org/10.1158/1535-7163.MCT-13-1093
  • Arnedos M, Shereen Denlinger C, Harb WA, Rixe O, Charles Morris J, Dy GK, Adjei AA, Pearlberg J, Follows S, Gabor Czibere A, et al. Abstract 2609: A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors. J Clin Oncol ASCO Annual Meeting. J Clin Oncol 2013; 31(suppl; abstr 2609)
  • Cleary JM, Jackson McRee A, O'Neil BH, Sharma S, Pearlberg J, Manoli S, Lloyd Kubasek W, Korn WM. Abstract 3076: A phase 1 study of MM-121 (a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3) in combination with cetuximab and irinotecan in patients with advanced cancers. J Clin Oncol ASCO Annual Meeting 2014; 32:5s
  • Sequist LV, Lopez-Chavez A, Doebele RC, Gray JE, Harb WA, Modiano MR, Jackman DM, Baggstrom M, Atmaca A, Felip E, et al. Abstract 8051: A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients. J Clin Oncol ASCO Annual Meeting 2014; 32:5s
  • Liu J, Ray-Coquard IA, Selle F, Poveda A, Cibula D, Hirte HW, Raspagliesi F, Gladieff L, Harter P, Schiavetto I, et al. Abstract 5519: A phase II randomized open-label study of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with weekly paclitaxel versus weekly paclitaxel in patients with platinum-resistant/refractory ovarian cancers. J Clin Oncol ASCO Annual Meeting 2014; 32:5s
  • Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D, et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 2013; 73:6024-35; PMID:23928993; http://dx.doi.org/10.1158/0008-5472.CAN-13-1198
  • Im S-A, Juric D, Baselga J, Kong A, Martin P, Lin CC, Dees EC, Schellens JHM, De Braud FG, Delgado L, et al. Abstract 2519: A phase 1 dose-escalation study of anti-HER3 monoclonal antibody LJM716 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast or gastric cancer. J Clin Oncol ASCO Annual Meeting 2014; 32:5s
  • Garrett JT, Sutton CR, Kurupi R, Bialucha CU, Ettenberg SA, Collins SD, Sheng Q, Wallweber J, Defazio-Eli L, Arteaga CL. Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. Cancer Res 2013; 73:6013-23; PMID:23918797; http://dx.doi.org/10.1158/0008-5472.CAN-13-1191
  • Vincent S, Fleet C, Bottega S, McIntosh D, Winston W, Chen T, Tyler S, Meetze K, Weiler S, Gyuris J. Abstract 2509: AV-203, a humanized ERBB3 inhibitory antibody inhibits ligand-dependent and ligand-independent ERBB3 signaling in vitro and in vivo. Proc AACR 103rd Annual Meeting. Cancer Res 2012; 72:2509; http://dx.doi.org/10.1158/1538-7445.AM2012-2509
  • Meetze K, Vincent S, Tyler S, Mazsa EK, Delpero AR, Bottega S, McIntosh D, Nicoletti R, Winston WM, Weiler S, et al. Neuregulin 1 Expression Is a Predictive Biomarker for Response to AV-203, an ERBB3 Inhibitory Antibody, in Human Tumor Models. Clin Cancer Res 2015; 21:1106-14; PMID:25542901; http://dx.doi.org/10.1158/1078-0432.CCR-14-2407
  • Sarantopoulos J, Gordon MS, Harvey RD, Sankhala KK, Malik L, Mahalingam D, Owonikoko TK, Lewis CM, Payumo F, Miller J, et al. First-in-human phase 1 dose-escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or advanced solid tumors. ASCO Meeting Abstracts 2014; 32:11113
  • Aurisicchio L, Marra E, Luberto L, Carlomosti F, De Vitis C, Noto A, Gunes Z, Roscilli G, Mesiti G, Mancini R, et al. Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors. J Cell Physiol 2012; 227:3381-8; PMID:22213458; http://dx.doi.org/10.1002/jcp.24037
  • Fattore L, Malpicci D, Marra E, Camerlingo R, Roscilli G, Belleudi F, Ribas A, Mancini R, Torrisi MR, Aurisicchio L, et al. ErbB3 plays a key role in the early phase of establishment of resistance to BRAF and/or MEK inhibitors. J Transl Med 2015; 13:2041; http://dx.doi.org/10.1186/1479-5876-13-S1-K3
  • Sala G, Traini S, D'Egidio M, Vianale G, Rossi C, Piccolo E, Lattanzio R, Piantelli M, Tinari N, Natali PG, et al. An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene 2012; 31:1275-86; PMID:21822299; http://dx.doi.org/10.1038/onc.2011.322
  • Sala G, Rapposelli IG, Ghasemi R, Piccolo E, Traini S, Capone E, Rossi C, Pelliccia A, Di Risio A, D'Egidio M, et al. EV20, a Novel Anti-ErbB-3 Humanized Antibody, Promotes ErbB-3 Down-Regulation and Inhibits Tumor Growth In Vivo. Transl Oncol 2013; 6:676-84; PMID:24466370; http://dx.doi.org/10.1593/tlo.13475
  • Zhang L, Castanaro C, Luan B, Yang K, Fan L, Fairhurst JL, Rafique A, Potocky TB, Shan J, Delfino FJ, et al. ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models. Mol Cancer Therapeutics 2014; 13:1345-55; http://dx.doi.org/10.1158/1535-7163.MCT-13-1033
  • Papadopoulos KP, Adjei AA, Rasco DW, Liu L, Kao RJ, Brownstein CM, DiCioccio AT, Lowy I, Trail P, Wang D. Phase 1 study of REGN1400 (anti-ErbB3) combined with erlotinib or cetuximab in patients (pts) with advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or head and neck cancer (SCCHN). ASCO Meeting Abstracts 2014; 32:2516
  • Blackburn E, Zona S, Murphy ML, Brown IR, Chan SK, Gullick WJ. A monoclonal antibody to the human HER3 receptor inhibits Neuregulin 1-β binding and co-operates with Herceptin in inhibiting the growth of breast cancer derived cell lines. Breast Cancer Res Treatment 2012; 134:53-9; http://dx.doi.org/10.1007/s10549-011-1908-1
  • Lazrek Y, Dubreuil O, Garambois V, Gaborit N, Larbouret C, Le Clorennec C, Thomas G, Leconet W, Jarlier M, Pugniere M, et al. Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation. Neoplasia 2013; 15:335-47; PMID:23479511; http://dx.doi.org/10.1593/neo.121960
  • Thomas G, Chardès T, Gaborit N, Mollevi C, Leconet W, Robert B, Radosevic-Robin N, Penault-Llorca F, Gongora C, Colombo P-E, et al. HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models. Oncotarget 2014; 5:7138-48; PMID:25216528; http://dx.doi.org/10.18632/oncotarget.2231
  • Bossenmaier B, Friess T, Gerdes CA, Kolm I, Dimoudis N, Lifke V, Reiff U, Moessner E, Hoelzlwimmer G, von Hirschheydt T, et al. Abstract 2508: GE-huMab-HER3, a novel humanized, glycoengineered HER3 antibody with enhanced ADCC and superior preclinical in vitro and in vivo efficacy. Proc AACR 103rd Annual Meeting 2012. Cancer Res 2012; 72:2508; http://dx.doi.org/10.1158/1538-7445.AM2012-2508
  • Mirschberger C, Schiller CB, Schraml M, Dimoudis N, Friess T, Gerdes CA, Reiff U, Lifke V, Hoelzlwimmer G, Kolm I, et al. RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res 2013; 73:5183-94; PMID:23780344; http://dx.doi.org/10.1158/0008-5472.CAN-13-0099
  • Meulendijks D, Lolkema MPJK, Voest EE, De Jonge MJ, Sleijfer S, Schellens JH, Fleitas T, Cervantes-Ruiperez A, Martinez-Garcia M, Taus A, et al. A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein. ASCO Meeting Abstracts 2013; 31:2522
  • Clarke N, Hopson C, Hahn A, Sully K, Germaschewski F, Yates J, Akinseye C, Mangatt B, Jonak Z, Matheny C. Abstract 300: Preclinical pharmacologic characterization of GSK2849330, a monoclonal AccretaMab® antibody with optimized ADCC and CDC activity directed against HER3. Proc 26th EORTC – NCI – AACR Symposium Mol Targets Cancer Therapeutics 2014; 50(6 Suppl):98-9
  • Gerdes CA, Nicolini VG, Herter S, van Puijenbroek E, Lang S, Roemmele M, Moessner E, Freytag O, Friess T, Ries CH, et al. GA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab. Clin Cancer Res 2013; 19:1126-38; PMID:23209031; http://dx.doi.org/10.1158/1078-0432.CCR-12-0989
  • Cervantes-Ruiperez A, Markman B, Siena S, Pericay C, Aprile G, Bridgewater JA, Cubillo A, Waterston AM, Garcia-Carbonero R, Kozloff M, et al. The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC). ASCO Meeting Abstracts 2012; 30:TPS3637
  • Ben-Kasus T, Schechter B, Lavi S, Yarden Y, Sela M. Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: relevance of receptor endocytosis. Proc Natl Acad Sci USA 2009; 106:3294-9; PMID:19218427; http://dx.doi.org/10.1073/pnas.0812059106
  • Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, Sela M, Yarden Y. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci USA 2005; 102:1915-20; PMID:15684082; http://dx.doi.org/10.1073/pnas.0409610102
  • Spiridon CI, Ghetie MA, Uhr J, Marches R, Li JL, Shen GL, Vitetta ES. Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin Cancer Res 2002; 8:1720-30; PMID:12060609
  • Klapper LN, Vaisman N, Hurwitz E, Pinkas-Kramarski R, Yarden Y, Sela M. A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors. Oncogene 1997; 14:2099-109; PMID:9160890; http://dx.doi.org/10.1038/sj.onc.1201029
  • Kasprzyk PG, Song SU, Di Fiore PP, King CR. Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res 1992; 52:2771-6; PMID:1349849
  • Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372:724-34; PMID:25693012; http://dx.doi.org/10.1056/NEJMoa1413513
  • Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Eng J Med 2012; 366:109-19; http://dx.doi.org/10.1056/NEJMoa1113216
  • Pedersen MW, Jacobsen HJ, Koefoed K, Dahlman A, Kjaer I, Poulsen TT, Meijer PJ, Nielsen LS, Horak ID, Lantto J, et al. Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance. Mol Cancer Therapeutics 2015; 14:669-80; http://dx.doi.org/10.1158/1535-7163.MCT-14-0697
  • Ferraro DA, Gaborit N, Maron R, Cohen-Dvashi H, Porat Z, Pareja F, Lavi S, Lindzen M, Ben-Chetrit N, Sela M, et al. Inhibition of triple-negative breast cancer models by combinations of antibodies to EGFR. Proc Natl Acad Sci USA 2013; 110:1815-20; PMID:23319610; http://dx.doi.org/10.1073/pnas.1220763110
  • Skartved NJ, Jacobsen HJ, Pedersen MW, Jensen PF, Sen JW, Jorgensen TK, Hey A, Kragh M. Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor. Clin Cancer Res 2011; 17:5962-72; PMID:21825041; http://dx.doi.org/10.1158/1078-0432.CCR-11-1209
  • Iida M, Brand TM, Starr MM, Li C, Huppert EJ, Luthar N, Pedersen MW, Horak ID, Kragh M, Wheeler DL. Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab. Neoplasia 2013; 15:1196-206; PMID:24204198; http://dx.doi.org/10.1593/neo.131584
  • Pedersen MW, Jacobsen HJ, Koefoed K, Hey A, Pyke C, Haurum JS, Kragh M. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res 2010; 70:588-97; PMID:20068188; http://dx.doi.org/10.1158/0008-5472.CAN-09-1417
  • Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Rosello S, Tops BB, van der Post RS, Argiles G, Skartved NJ, et al. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer. Cancer Discov 2015; 5:598-609; PMID:25962717; http://dx.doi.org/10.1158/2159-8290.CD-14-1432
  • Gaborit N, Abdul-Hai A, Mancini M, Lindzen M, Lavi S, Leitner O, Mounier L, Chentouf M, Dunoyer S, Ghosh M, et al. Examination of HER3 targeting in cancer using monoclonal antibodies. Proc Natl Acad Sci USA 2015; 112:839-44; PMID:25564668; http://dx.doi.org/10.1073/pnas.1423645112
  • D'Souza JW, Reddy S, Goldsmith LE, Shchaveleva I, Marks JD, Litwin S, Robinson MK. Combining anti-ERBB3 antibodies specific for domain I and domain III enhances the anti-tumor activity over the individual monoclonal antibodies. PloS One 2014; 9:e112376; PMID:25386657; http://dx.doi.org/10.1371/journal.pone.0112376
  • Schaefer G, Haber L, Crocker LM, Shia S, Shao L, Dowbenko D, Totpal K, Wong A, Lee CV, Stawicki S, et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 2011; 20:472-86; PMID:22014573; http://dx.doi.org/10.1016/j.ccr.2011.09.003
  • Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, Harari PM. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res 2013; 73:824-33; PMID:23172311; http://dx.doi.org/10.1158/0008-5472.CAN-12-1611
  • Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, Weitsman G, Barber P, Vojnovic B, Ellis H, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal 2014; 7:ra29; PMID:24667376
  • Juric D, Dienstmann R, Cervantes A, Hidalgo M, Messersmith W, Blumenschein GR, Jr., Tabernero J, Roda D, Calles A, Jimeno A, et al. Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors. Clin Cancer Res 2015; 21:2462-70; PMID:26034219; http://dx.doi.org/10.1158/1078-0432.CCR-14-2412
  • Fayette J, Wirth LJ, Oprean C, Hitt R, Udrea A, Jimeno A, Rischin D, Nutting C, Harari PM, Csőszi T, et al. Randomized phase II study of MEHD7945A (MEHD) vs cetuximab (Cet) in >= 2nd-line recurrent/metastatic squamous cell Carcinoma of the head & neck Annals of Oncology. ESMO 2014; 25:iv340-iv56
  • Hill AG, Findlay M, Burge M, Jackson C, Garcia Alfonso P, Samuel L, Ganju V, Karthaus M, Amatu A, Jeffery M, et al. CT110 - Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). In: AACR, ed. 106th Annual Meeting of the American Association for Cancer Research. Philadelphia, PA, 2015
  • McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, Zhang B, Luus L, Overland R, Nguyen S, et al. Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Therapeutics 2012; 11:582-93; http://dx.doi.org/10.1158/1535-7163.MCT-11-0820
  • Richards DA, Braiteh FS, Garcia AA, Denlinger CS, Conkling PR, Edenfield WJ, Anthony SP, Hellerstedt BA, Raju RN, Becerra C, et al. A phase 1 study of MM-111, a bispecific HER2/HER3 antibody fusion protein, combined with multiple treatment regimens in patients with advanced HER2-positive solid tumors. ASCO Meeting Abstracts 2014; 32:651
  • Fitzgerald JB, Johnson BW, Baum J, Adams S, Iadevaia S, Tang J, Rimkunas V, Xu L, Kohli N, Rennard R, et al. MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Therapeutics 2014; 13:410-25; http://dx.doi.org/10.1158/1535-7163.MCT-13-0255
  • Hu S, Fu W, Xu W, Yang Y, Cruz M, Berezov SD, Jorissen D, Takeda H, Zhu W. Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk. Cancer Res 2015; 75:159-70; PMID:25371409; http://dx.doi.org/10.1158/0008-5472.CAN-14-1670
  • Kang JC, Poovassery JS, Bansal P, You S, Manjarres IM, Ober RJ, Ward ES. Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. Mabs 2014; 6:340-53; PMID:24492289; http://dx.doi.org/10.4161/mabs.27658
  • Jacobsen HJ, Poulsen TT, Dahlman A, Kjaer I, Koefoed K, Sen JW, Weilguny D, Bjerregaard B, Andersen CR, Horak ID, et al. Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2 and HER3 Effectively Overcomes Tumor Heterogeneity and Plasticity. Clin Cancer Res 2015; 21(18):4110-22; PMID:25908781; http://dx.doi.org/10.1158/1078-0432.CCR-14-3312
  • Mancini M, Gaborit N, Lindzen M, Meir Salame T, Dall’Ora M, Sevilla-Sharon M, Abdul-Hai A, Downward J, Yarden Y. Combining Three Antibodies Nullifies Feedback and Inhibits Erlotinib Resistant Lung Cancer. Sci Signal 2015; 8(379):ra53 in press; PMID:26038598; http://dx.doi.org/10.1126/scisignal.aaa0725
  • Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biozztechnol 2012; 30:679-92; http://dx.doi.org/10.1038/nbt.2284
  • Aurisicchio L, Marra E, Roscilli G, Mancini R, Ciliberto G. The promise of anti-ErbB3 monoclonals as new cancer therapeutics. Oncotarget 2012; 3:744-58; PMID:22889873; http://dx.doi.org/10.18632/oncotarget.550

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.