ERKed by too much signaling: from oncogenic driver to therapeutic vulnerability

Extracellular regulated kinase (ERK) signaling is a major driver of cancer development. Mutations accumulated in oncogenes upstream of ERK can promote and sustain tumorigenesis by providing a sustained proliferative signal, helping cells resist death, and inducing angiogenesis. Therapeutic strategies for cancers with dysregulated ERK signaling have focused on inhibiting upstream-mutated oncogenes as a means of depriving tumors of these essential survival cues. While these strategies have demonstrated initial clinical success in patients, they also represent an incomplete understanding of the more nuanced role ERK signaling plays in tumor cell homeostasis. It is now understood that increased ERK signaling can also function as a tumor suppressor by inducing proliferative arrest outside of the framework of oncogene-induced senescence. In this review, we highlight current research describing the vulnerability of cancer cells to ERK hyperactivation induced toxicity and offer insight on how ERK rewiring may be leveraged for the development of new therapeutic strategies for patients.