Conclusion
Our preclinical findings will accelerate the initialization of clinical trials to use combination of cobimetinib and paclitaxel for treating cervical cancer. Our work also emphasizes the therapeutic value of targeting MAPK/ERK to overcome chemoresistance in cervical cancer.
Methods
The in vitro and in vivo efficacies of cobimetinib were examined using cervical cancer cell cultures and xenograft mouse model. Its combination with paclitaxel was analyzed using the combination index. Immunoblotting was performed on MAPK and ERK pathways.
Results
Cobimetinib displays a potent anti-cervical cancer activity in a panel of cell lines regardless of cellular origin and HPV presence, and its combination with paclitaxel is synergistic in inhibiting cervical cancer cells. This is achieved by the growth inhibition and caspase-dependent apoptosis induction, through inhibiting MAPK/ERK activation. In addition, paclitaxel activates ERK in cervical cancer cells, and this can be reversed by cobimetinib. We finally confirm the efficacy of cobimetinib alone and its combination with paclitaxel in the cervical cancer xenograft mouse model.