Application of Trastuzumab Emtansine in HER-2-positive and KRAS/BRAF-mutated Colon Cancer Cells

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.