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Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration.

Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ, Hadari Y, Alvarado D, Schlessinger J
Proc Natl Acad Sci U S A 112 13225-30 (2015)
Cited: 27 times
EuropePMC logo PMID: 26460020

Abstract

ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.

Reviews - 5cus mentioned but not cited (1)

  1. Insulin and epidermal growth factor receptor family members share parallel activation mechanisms. Ferguson KM, Hu C, Lemmon MA. Protein Sci 29 1331-1344 (2020)

Articles - 5cus mentioned but not cited (2)

  1. Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration. Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ, Hadari Y, Alvarado D, Schlessinger J. Proc Natl Acad Sci U S A 112 13225-13230 (2015)
  2. Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5. Radom F, Vonrhein C, Mittl PRE, Plückthun A. Acta Crystallogr F Struct Biol Commun 77 192-201 (2021)


Reviews citing this publication (4)

  1. Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Haikala HM, Jänne PA. Clin Cancer Res 27 3528-3539 (2021)
  2. A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer. Mota JM, Collier KA, Barros Costa RL, Taxter T, Kalyan A, Leite CA, Chae YK, Giles FJ, Carneiro BA. Oncotarget 8 89284-89306 (2017)
  3. Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds. Malm M, Frejd FY, Ståhl S, Löfblom J. MAbs 8 1195-1209 (2016)
  4. HER3 in cancer: from the bench to the bedside. Gandullo-Sánchez L, Ocaña A, Pandiella A. J Exp Clin Cancer Res 41 310 (2022)

Articles citing this publication (20)

  1. Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer. Wang Z, Goto Y, Allevato MM, Wu VH, Saddawi-Konefka R, Gilardi M, Alvarado D, Yung BS, O'Farrell A, Molinolo AA, Duvvuri U, Grandis JR, Califano JA, Cohen EEW, Gutkind JS. Nat Commun 12 2383 (2021)
  2. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. Swaney DL, Ramms DJ, Wang Z, Park J, Goto Y, Soucheray M, Bhola N, Kim K, Zheng F, Zeng Y, McGregor M, Herrington KA, O'Keefe R, Jin N, VanLandingham NK, Foussard H, Von Dollen J, Bouhaddou M, Jimenez-Morales D, Obernier K, Kreisberg JF, Kim M, Johnson DE, Jura N, Grandis JR, Gutkind JS, Ideker T, Krogan NJ. Science 374 eabf2911 (2021)
  3. The ERK/MAPK pathway is overexpressed and activated in gallbladder cancer. Buchegger K, Silva R, López J, Ili C, Araya JC, Leal P, Brebi P, Riquelme I, Roa JC. Pathol Res Pract 213 476-482 (2017)
  4. Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial. Tchekmedyian V, Dunn L, Sherman E, Baxi SS, Grewal RK, Larson SM, Pentlow KS, Haque S, Tuttle RM, Sabra MM, Fish S, Boucai L, Walters J, Ghossein RA, Seshan VE, Knauf JA, Pfister DG, Fagin JA, Ho AL. Thyroid 32 273-282 (2022)
  5. Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial. Burtness B, Haddad R, Dinis J, Trigo J, Yokota T, de Souza Viana L, Romanov I, Vermorken J, Bourhis J, Tahara M, Martins Segalla JG, Psyrri A, Vasilevskaya I, Nangia CS, Chaves-Conde M, Kiyota N, Homma A, Holeckova P, Del Campo JM, Asarawala N, Nicolau UR, Rauch D, Even C, Wang B, Gibson N, Ehrnrooth E, Harrington K, Cohen EEW, LUX-Head & Neck 2 investigators. JAMA Oncol 5 1170-1180 (2019)
  6. Inhibition of HER3 activation and tumor growth with a human antibody binding to a conserved epitope formed by domain III and IV. Schmitt LC, Rau A, Seifert O, Honer J, Hutt M, Schmid S, Zantow J, Hust M, Dübel S, Olayioye MA, Kontermann RE. MAbs 9 831-843 (2017)
  7. ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC. Alvarado D, Ligon GF, Lillquist JS, Seibel SB, Wallweber G, Neumeister VM, Rimm DL, McMahon G, LaVallee TM. PLoS One 12 e0181356 (2017)
  8. HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma. Meister KS, Godse NR, Khan NI, Hedberg ML, Kemp C, Kulkarni S, Alvarado D, LaVallee T, Kim S, Grandis JR, Duvvuri U. Sci Rep 9 9130 (2019)
  9. AXL regulates neuregulin1 expression leading to cetuximab resistance in head and neck cancer. Iida M, McDaniel NK, Kostecki KL, Welke NB, Kranjac CA, Liu P, Longhurst C, Bruce JY, Hong S, Salgia R, Wheeler DL. BMC Cancer 22 447 (2022)
  10. Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma. Baro M, Lopez Sambrooks C, Burtness BA, Lemmon MA, Contessa JN. Mol Cancer Ther 18 2124-2134 (2019)
  11. ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1). Hayes DA, Kunde DA, Taylor RL, Pyecroft SB, Sohal SS, Snow ET. PLoS One 12 e0177919 (2017)
  12. Crystal structures of a llama VHH antibody BCD090-M2 targeting human ErbB3 receptor. Eliseev IE, Yudenko AN, Vysochinskaya VV, Svirina AA, Evstratyeva AV, Drozhzhachih MS, Krendeleva EA, Vladimirova AK, Nemankin TA, Ekimova VM, Ulitin AB, Lomovskaya MI, Yakovlev PA, Bukatin AS, Knyazev NA, Moiseenko FV, Chakchir OB. F1000Res 7 57 (2018)
  13. Development of a novel, fully human, anti-PCSK9 antibody with potent hypolipidemic activity by utilizing phage display-based strategy. Xu M, Lei G, Chen M, Wang K, Lv W, Zhang P, Hu T, Gao J, Lu C, Mei Y, Xu Z, Bai Z, Hu H, Jiang Y, Tan S. EBioMedicine 65 103250 (2021)
  14. Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response. Turowec JP, Lau EWT, Wang X, Brown KR, Fellouse FA, Jawanda KK, Pan J, Moffat J, Sidhu SS. J Biol Chem 294 1396-1409 (2019)
  15. Targeting ErbB3 Receptor in Cancer with Inhibitory Antibodies from Llama. Eliseev IE, Ukrainskaya VM, Yudenko AN, Mikushina AD, Shmakov SV, Afremova AI, Ekimova VM, Vronskaia AA, Knyazev NA, Shamova OV. Biomedicines 9 1106 (2021)
  16. A small molecule inhibitor of HER3: a proof-of-concept study. Colomba A, Fitzek M, George R, Weitsman G, Roberts S, Zanetti-Domingues L, Hirsch M, Rolfe DJ, Mehmood S, Madin A, Claus J, Kjaer S, Snijders AP, Ng T, Martin-Fernandez M, Smith DM, Parker PJ. Biochem J 477 3329-3347 (2020)
  17. Synthesis of Multiple Bispecific Antibody Formats with Only One Single Enzyme Based on Enhanced Trypsiligase. Voigt J, Meyer C, Bordusa F. Int J Mol Sci 23 3144 (2022)
  18. Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands. Brahimi F, Galan A, Jmaeff S, Barcelona PF, De Jay N, Dejgaard K, Young JC, Kleinman CL, Thomas DY, Saragovi HU. iScience 23 101447 (2020)
  19. Coordinate transcriptional regulation of ErbB2/3 by C-terminal binding protein 2 signals sensitivity to ErbB2 inhibition in pancreatic adenocarcinoma. Chougoni KK, Park H, Damle PK, Mason T, Cheng B, Dcona MM, Szomju B, Dozmorov MG, Idowu MO, Grossman SR. Oncogenesis 12 53 (2023)
  20. Transcriptome sequencing reveals novel molecular features of SLE severity. Zhang X, Zhang J, Pan Z, Zhang Y, Xu X, Sheng Y, Zhu Z, Zhou F, Wen L. Front Genet 14 1121359 (2023)


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