Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of some anti-cancer drugs and leads to discontinuation of chemotherapy and detrimental dose reductions, thereby affecting the quality of life of cancer patients. Currently, no treatment can effectively prevent or treat chemotherapy-induced neuropathy. Therefore, understanding its underlying molecular mechanisms may help to identify novel therapies for treating it. Some disease-induced neuropathy involve the activation of mitogen-activated protein kinases (MAPKs), such as extracellular-regulated protein kinase 1/2 (ERK1/2). In the present study, we investigated whether ERK1/2 inhibition can prevent chemotherapy-induced neuropathy. We found that trametinib, an MEK inhibitor, suppressed oxaliplatin-, paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, treatment with oxaliplatin, paclitaxel, vincristine, or bortezomib enhanced ERK1/2 and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord lumbar segments 4-6, and when combined with trametinib, can prevent chemotherapy-induced neuropathy via the suppression of ERK1/2 activation, but does not affect JNK activation. In conclusion, we demonstrated that the disruption of this pathway by MEK inhibitors suppresses oxaliplatin, paclitaxel, vincristine-, and bortezomib-induced neuropathy. This suggests that inhibition of the MEK/ERK pathway could prevent chemotherapy-induced neuropathy and MEK inhibitors could be used in combination with anti-tumor drugs during pharmacotherapy.