GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer
- Gastric Cancer. 2019 Sep;22(5):932-940. doi: 10.1007/s10120-019-00943-x.
- 1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
- 2. MOGAM Institute for Biomedical Research, Yongin, Gyeonggi-do, South Korea.
- 3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. [email protected].
- 4. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea. [email protected].
- 5. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
- # Contributed equally.
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.