The RAF-MEK-ERK Pathway: Targeting ERK to Overcome Obstacles of Effective Cancer Therapy

AIM: Currently, dozens of BRAF inhibitors and MEK inhibitors targeting RAF-MEK-ERK pathway have been introduced into clinical trials for cancer therapy. However, after 6-8 months of initial response, acquired drug resistance among the majority of those treated patients sharply diminished their clinical efficacy. DISCUSSION: Important mechanisms responsible for acquired resistance of BRAF inhibitors and MEK inhibitors have been elucidated. Continually, ERK1/2 locates in the critical position and features unique characteristics, such as activating hundreds of substrates, participating in feedback regulation, being catalyzed by MEK specifically and no acquired resistant mutation. CONCLUSION: Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway.