Comprehensive Analysis of ERK1/2 Substrates for Potential Combination Immunotherapies

Abstract

Recent clinical and therapeutic success with RAF and MEK1/2 inhibitors has revolutionized the existing treatment schemes for previously incurable cancers like melanomas. However, the overall therapeutic efficacies are still largely compromised by the dose-limiting side effects and emerging drug resistance mechanisms. Accumulating evidence has revealed the intricate nature of the RAS-RAF-MEK1/2-ERK1/2 pathway, such as activation mechanisms, kinase-substrate relationships, crosstalk with parallel signaling pathways, feedback regulations, and intimate interplay with immune responses. Limited strategies are currently available to exploit the benefits of combining RAF-MEK1/2-ERK1/2 pathway inhibitors with other targeted therapies or immunotherapies. Here, we compiled the kinase-substrate relationships and analyzed the intricate signaling networks of the renowned pathway, providing an integrated and simplified visualization, to reveal the potentials of RAS-RAF-MEK1/2-ERK1/2-based combination therapies.

Keywords: RAF-MEK-ERK pathway; bypass signaling; combination therapy; crosstalk; drug resistance; kinase–substrate relationship.