title: Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma.
abstract: The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened 12 HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent antitumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT, and ERK in vivo. Our work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.
authors.affiliation: Authors' Affiliations: State Key Laboratory of Oncology in Southern China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China; Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Ning
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Quest Diagnostics, Tucker, Georgia; and.
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Guoqing
authors.initials: G
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Mohammad Aminur
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Hongzheng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: A R M Ruhul
authors.initials: AR
authors.lastname: Amin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Nannapaneni
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory School of Public Health, Atlanta, Georgia;
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory School of Public Health, Atlanta, Georgia;
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Authors' Affiliations: State Key Laboratory of Oncology in Southern China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China;
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine; gzchen@emory.edu nfsaba@emory.edu.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine; gzchen@emory.edu nfsaba@emory.edu.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020893:Receptor, ErbB-3; D000068818:Cetuximab
references.citation: Cancer Cell. 2010 Mar 16;17(3):298-310
references.pmid: 20227043
references.citation: Acta Otolaryngol. 2013 Jul;133(7):761-71
references.pmid: 23638950
references.citation: Int J Cancer. 2012 Aug 15;131(4):956-69
references.pmid: 21918971
references.citation: Cancer Res. 2002 Dec 15;62(24):7350-6
references.pmid: 12499279
references.citation: Clin Cancer Res. 2011 Dec 1;17(23):7248-64
references.pmid: 21868764
references.citation: J Clin Invest. 2008 Jul;118(7):2609-19
references.pmid: 18568074
references.citation: Nature. 2007 Jan 25;445(7126):437-41
references.pmid: 17206155
references.citation: Am J Clin Pathol. 2005 Jul;124(1):71-6
references.pmid: 15923166
references.citation: Cancer Res. 2013 Aug 1;73(15):4791-800
references.pmid: 23749640
references.citation: Int J Cancer. 2008 Sep 1;123(5):1005-14
references.pmid: 18546267
references.citation: J Transl Med. 2011 Jul 29;9:126
references.pmid: 21801427
references.citation: Clin Cancer Res. 2006 Jul 1;12(13):4103-11
references.pmid: 16818711
references.citation: Sci Transl Med. 2011 Sep 7;3(99):99ra86
references.pmid: 21900593
references.citation: Clin Cancer Res. 2012 Sep 1;18(17):4589-99
references.pmid: 22829201
references.citation: Cancer Res. 1993 Aug 1;53(15):3579-84
references.pmid: 8339264
references.citation: Cancer Res. 2011 Nov 15;71(22):7103-12
references.pmid: 21975930
references.citation: Cancer Res. 2002 Jan 1;62(1):200-7
references.pmid: 11782378
references.citation: J Clin Oncol. 2007 Jun 1;25(16):2171-7
references.pmid: 17538161
references.citation: Clin Cancer Res. 2007 Sep 1;13(17):4964-73
references.pmid: 17785546
references.citation: Semin Radiat Oncol. 2009 Jan;19(1):63-8
references.pmid: 19028347
references.citation: Chemother Res Pract. 2012;2012:817304
references.pmid: 23198146
references.citation: Nat Med. 2012 Jan 22;18(2):221-3
references.pmid: 22270724
references.citation: Cancer Res. 2010 Mar 15;70(6):2485-94
references.pmid: 20215504
references.citation: Sci Signal. 2009 Jun 30;2(77):ra31
references.pmid: 19567914
references.citation: N Engl J Med. 2008 Sep 11;359(11):1116-27
references.pmid: 18784101
references.citation: Cancer Res. 2005 Nov 1;65(21):9953-61
references.pmid: 16267020
references.citation: J Clin Oncol. 2000 Nov 1;18(21 Suppl):47S-53S
references.pmid: 11060327
references.citation: Breast Cancer Res. 2013;15(5):R101
references.pmid: 24168763
references.citation: Oncogene. 2008 Jun 26;27(28):3944-56
references.pmid: 18297114
references.citation: Eur J Cancer. 2014 Apr;50(6):1100-11
references.pmid: 24424107
references.citation: Head Neck Pathol. 2012 Jul;6 Suppl 1:S121-8
references.pmid: 22782231
references.citation: Mol Cancer Ther. 2011 Nov;10(11):2124-34
references.pmid: 21878657
references.citation: Trends Biochem Sci. 2006 Jun;31(6):342-8
references.pmid: 16679021
references.citation: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references.pmid: 15761078
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Am J Pathol. 1993 Aug;143(2):401-9
references.pmid: 7688183
references.citation: Br J Cancer. 2011 Aug 9;105(4):523-33
references.pmid: 21792199
references.citation: Mol Cancer Ther. 2011 Dec;10(12):2437-48
references.pmid: 21980128
references.citation: Cancer Res. 2013 Jan 15;73(2):834-43
references.pmid: 23172312
references.citation: Science. 2007 May 18;316(5827):1039-43
references.pmid: 17463250
references.citation: J Biol Chem. 2010 Nov 5;285(45):34557-65
references.pmid: 20826787
references.citation: Cancer Cell. 2011 Oct 18;20(4):423-5
references.pmid: 22014569
references.citation: Head Neck. 2011 Apr;33(4):504-12
references.pmid: 20652977
references.citation: Cancer Cell. 2011 Oct 18;20(4):472-86
references.pmid: 22014573
references.citation: Oncogene. 2010 Sep 16;29(37):5135-45
references.pmid: 20622897
references.citation: Eur J Cancer. 2011 May;47(8):1231-43
references.pmid: 21273060
references.citation: Nat Med. 2012 Feb 06;18(2):199-200
references.pmid: 22310681
references.citation: N Engl J Med. 2006 Feb 9;354(6):567-78
references.pmid: 16467544
references.citation: J Clin Oncol. 2006 Jun 10;24(17):2606-11
references.pmid: 16763272
references.citation: Mol Cancer. 2013 Nov 11;12(1):134
references.pmid: 24215614