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Application of trastuzumab emtansine in HER‐2–positive and KRAS/BRAF‐mutated colon cancer cells
Author(s) -
Chung YuanChiang,
Chiu HsiHsiung,
Wei WanChen,
Chang KingJen,
Chao WeiTing
Publication year - 2020
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.13255
Subject(s) - cetuximab , trastuzumab , trastuzumab emtansine , cancer research , kras , colorectal cancer , cancer , medicine , antibody drug conjugate , antibody , cancer cell , pharmacology , breast cancer , monoclonal antibody , immunology
Background Trastuzumab emtansine (T‐DM1) is an antibody‐drug conjugate (ADC) for the treatment of human epidermal growth factor receptor 2 (HER‐2)–positive breast cancer. T‐DM1 is based on the trastuzumab antibody and delivers a toxic agent into breast cancer cells through endocytic mechanism. This study evaluated whether T‐DM1 can be used in HER‐2–positive colon cancer cells which harbour KRAS/ BRAF mutation with limited treatment. Materials and Methods LS174T and HT‐29 which are KRAS and BRAF mutant HER‐2–positive colon cancer cells were used in this study. Cells were first treated with T‐DM1; cetuximab and trastuzumab were applied for comparison, the effect of drug sensitivity was determined. Cells were then transfected with plasmid to overexpress HER‐2 or the endocytic protein, caveolin‐1 or furthermore pretreated with metformin to examine the effect of T‐DM1 efficacy. Finally, a xenograft mouse model was used to evaluate the drug efficacy in vivo. Results The results showed that T‐DM1 had better inhibitory effect than cetuximab and trastuzumab on LS174T and HT‐29 cells. HER‐2 or caveolin‐1 overexpression with plasmid in the cells to increase T‐DM1 recognition or internalization can increase the sensitivity to T‐DM1. When cells were pretreated with metformin, caveolin‐1 expression was induced and promoted T‐DM1 uptake and enhanced cell toxicity. In xenograft mouse model, combined treatment of T‐DM1 and metformin had apparent inhibitory effect on subcutaneous tumour growth. Conclusion The results of this study suggested that T‐DM1 has potential in the treatment of HER‐2–positive colon cancer cells, and application of metformin has therapeutic benefits during T‐DM1 treatment.