ERK1/2-targeted Cancer therapies: Recent advances, potential drug resistance, and applicability analysis of emerging...

As the terminal effector of the RAS-RAF-MEK-ERK signaling cascade, extracellular signal-regulated kinase 1/2 (ERK1/2) plays a central role in transmitting oncogenic signals, and its dysregulated activation directly drives tumor initiation, disease progression, and poor clinical outcomes. Although inhibitors targeting upstream nodes, such as RAF and MEK have demonstrated clinical benefit, the frequent emergence of acquired resistance remains a major barrier, ultimately limiting their long-term therapeutic effectiveness. Consequently, direct inhibition of ERK1/2 has gained increasing attention as a promising strategy, offering not only potent suppression of MAPK pathway activity but also the potential to overcome resistance driven by upstream genetic alterations. Despite its therapeutic promise, the clinical development of ERK1/2 inhibitors is confronted with several significant challenges. Firstly, although first-generation ATP-competitive inhibitors such as Ulixertinib have shown antitumor activity in early-phase trials, their efficacy varies widely across patient populations and is often accompanied by mechanism-based toxicities (including rash and diarrhea), highlighting a substantial disconnection between preclinical predictions and clinical outcomes. Secondly, tumor cells can acquire resistance to ERK inhibition through a broad spectrum of adaptive responses, including activation of bypass signaling pathways, engagement of compensatory feedback loops, and emergence of ERK mutations that diminish drug potency. These resistance mechanisms collectively pose a major obstacle to durable therapeutic responses. This review aims to provide a comprehensive and forward-looking overview of the current landscape of ERK1/2-targeted therapies. It systematically evaluates small-molecule inhibitors under clinical investigation, offering an in-depth analysis of candidates that have reached or are approaching clinical development and identifying key factors underlying their success or failure. Building on this foundation, the review provides a detailed examination of the mechanisms underlying acquired resistance to ERK1/2 inhibitors, thereby offering a theoretical basis for designing rational combination therapies and strategies to overcome resistance. Furthermore, it highlights emerging technological advances, including innovative modalities that address limitations of traditional ATP-competitive inhibitors, such as targeted protein degradation (TPD) approaches. Collectively, this review seeks to outline a clearer roadmap toward realizing the full therapeutic potential of ERK1/2-targeted interventions in cancer treatment.