Gastric Cancer

, Volume 22, Issue 5, pp 932–940 | Cite as

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

  • Ji Eun Park
  • Mei Hua Jin
  • Minkyu Hur
  • Ah-Rong Nam
  • Ju-Hee Bang
  • Jonghwa Won
  • Do-Youn OhEmail author
  • Yung-Jue Bang
Original Article



EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC.


GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml.


GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model.


Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.


EGFR GC1118 Cetuximab Gastric cancer KRAS 



This study was supported by MOGAM Institute for Biomedical Research fund (Grant No. 06-2013-1580 and 06-2014-3250) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant number 2016R1D1A1A09918133).

Compliance with ethical standards

Conflict of interest

The authors disclose no potential conflicts of interest.

Ethical approval

All institutional and national guidelines for the care and use of laboratory animals were followed.


  1. 1.
    Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65:1566–84.CrossRefGoogle Scholar
  2. 2.
    Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012;12:553–63.CrossRefGoogle Scholar
  3. 3.
    Dokala A, Thakur SS. Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. Oncogene. 2017;36:2337–44.CrossRefGoogle Scholar
  4. 4.
    Kim MA, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52:738–46.CrossRefGoogle Scholar
  5. 5.
    Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490–99.CrossRefGoogle Scholar
  6. 6.
    Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, et al. Epirubicine, oxalipatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:481–89.CrossRefGoogle Scholar
  7. 7.
    Lim Y, Yoo J, Kim MS, Hur M, Lee EH, Hur HS, et al. GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands. Mol Cancer Ther. 2016;15:251–63.CrossRefGoogle Scholar
  8. 8.
    Takahashi N, Yamada Y, Taniguchi H, Fukahori M, Sasaki Y, Shoji H, et al. Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer. BMC Res Notes. 2014;7:271.CrossRefGoogle Scholar
  9. 9.
    Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673–84.CrossRefGoogle Scholar
  10. 10.
    Shimura T, Yoshida M, Fukuda S, Ebi M, Hirata Y, Mizoshita T, et al. Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion. BMC Cancer. 2012;12:205.CrossRefGoogle Scholar
  11. 11.
    Yotsumoto F, Sanui A, Fukami T, Shirota K, Horiuchi S, Tsujioka H, et al. Efficacy of ligand-based targeting for the EGF system in cancer. Anticancer Res. 2009;29:4879–85.Google Scholar
  12. 12.
    Baek MK, Kim MH, Jang HJ, Park JS, Chung IJ, Shin BA, et al. EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. Oncol Rep. 2008;20:1569–75.Google Scholar
  13. 13.
    Chakraborty S, Li L, Puliyappadamba VT, Guo G, Hatanpaa KJ, Mickey B, et al. Constitutive and ligand-induced EGFR signaling triggers distinct and mutually exclusive downstream signaling networks. Nat Commun. 2014;5:5811.CrossRefGoogle Scholar
  14. 14.
    Hotz B, Keilholz U, Fusi A, Buhr HJ, Hotz HG. In vitro and in vivo antitumor activity of cetuximab in human gastric cancer cell lines in relation to epidermal growth factor receptor (EGFR) expression and mutational phenotype. Gastric Cancer. 2012;15:252–64.CrossRefGoogle Scholar
  15. 15.
    Heindl S, Eggenstein E, Keller S, Kneissl J, Keller G, Mutze K, et al. Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines. J Cancer Res Clin Oncol. 2012;138:843–58.CrossRefGoogle Scholar
  16. 16.
    Kneissl J, Hartmann A, Pfarr N, Erlmeier F, Lorber T, Keller S, et al. Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. J Cancer Res Clin Oncol. 2017;143:573–600.CrossRefGoogle Scholar
  17. 17.
    Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532–6.CrossRefGoogle Scholar
  18. 18.
    Bardelli A, Jänne PA. The road to resistance: EGFR mutation and cetuximab. Nat Med. 2012;18:199–200.CrossRefGoogle Scholar
  19. 19.
    Arena S, Siravegna G, Mussolin B, Kearns JD, Wolf BB, Misale S, et al. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. Sci Transl Med. 2016;8:324ra14.CrossRefGoogle Scholar
  20. 20.
    Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1:508–23.CrossRefGoogle Scholar
  21. 21.
    Kasper S, Breitenbuecher F, Reis H, Brandau S, Worm K, Köhler J, et al. Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade. Oncogene. 2013;32:2873–81.CrossRefGoogle Scholar
  22. 22.
    Marzi L, Combes E, Vié N, Ayrolles-Torro A, Tosi D, Desigaud D,et al. FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer. Br J Cancer. 2016;115:1223–33.CrossRefGoogle Scholar
  23. 23.
    Ali M, Kaltenbrun E, Anderson GR, Stephens SJ, Arena S, Bardelli A, et al. Codon bias imposes a targetable limitations on KRAS-driven therapeutic resistance. Nat Commun. 2017;8:15617.CrossRefGoogle Scholar
  24. 24.
    Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, et al. LncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling. Nat Med. 2017;23:1331–41.CrossRefGoogle Scholar
  25. 25.
    Pozzi C, Cuomo A, Spadoni I, Magni E, Silvola A, Conte A, et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat Med. 2016;22:624–31.CrossRefGoogle Scholar
  26. 26.
    Trivedi S, Srivastava RM, Concha-Benavente F, Ferrone S, Garcia-Bates TM, Li J, et al. Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients. Clin Cancer Res. 2016;22:5229–37.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Ji Eun Park
    • 1
  • Mei Hua Jin
    • 1
  • Minkyu Hur
    • 3
  • Ah-Rong Nam
    • 1
  • Ju-Hee Bang
    • 1
  • Jonghwa Won
    • 3
  • Do-Youn Oh
    • 1
    • 2
    Email author
  • Yung-Jue Bang
    • 1
    • 2
  1. 1.Cancer Research InstituteSeoul National University College of MedicineSeoulSouth Korea
  2. 2.Department of Internal MedicineSeoul National University College of MedicineSeoulSouth Korea
  3. 3.MOGAM Institute for Biomedical ResearchYonginSouth Korea

Personalised recommendations