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At least 40% of human cancers are associated with aberrant ERK pathway activity (ERKp). Inhibitors targeting various effectors within the ERKp have been developed and explored for over two decades. Conversely, a substantial body of evidence suggests that both normal human cells and, notably to a greater extent, cancer cells exhibit susceptibility to hyperactivation of ERKp. However, this vulnerability of cancer cells remains relatively unexplored. In this review, we reexamine the evidence on the selective lethality of highly elevated ERKp activity in human cancer cells of varying backgrounds. We synthesize the insights proposed for harnessing this vulnerability of ERK-associated cancers for therapeutical approaches and contextualize these insights within established pharmacological cancer-targeting models. Moreover, we compile the intriguing preclinical findings of ERK pathway agonism in diverse cancer models. Lastly, we present a conceptual framework for target discovery regarding ERKp agonism, emphasizing the utilization of mutual exclusivity among oncogenes to develop novel targeted therapies for precision oncology. [ABSTRACT FROM AUTHOR]

Cancer-targeted therapies that inhibit oncogenic signaling often lead to resistance and recurrence. In a recent study, Dias et al. propose activating oncogenic pathways and inducing replication stress, resulting in cell death and tumor-suppressive mechanisms in colorectal cancer (CRC). This approach could spark a new wave of target discovery, and drug development and repurposing against cancer. [ABSTRACT FROM AUTHOR]