The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy

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. 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. 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.