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BRAF mutation is a common driver event in melanoma, rendering the tumors reliant on constitutive signaling through the MAp. pathway and the extracellular signal-regulated kinases (ERK) 1 and 2. Thus, MAPK pathway inhibitors that act through both ERK1 and ERK2 have become a key component of the therapeutic arsenal against melanoma, but their use is associated with dose-limiting toxicities. Here, Crowe and colleagues demonstrate that BRAF-mutant melanoma is specifically reliant on ERK2 signaling. Targeted ERK2 ablation resulted in transcriptomic and proteomic alterations that aligned with those effected by full MAPK pathway inhibitors, whereas targeted ERK1 ablation produced a distinct set of responses. Both isoforms promoted cell viability, but ERK2 loss suppressed MAPK pathway activity and cell proliferation more effectively than ERK1 loss. Moreover, ERK2 was shown to compensate for ERK1 depletion in the context of BRAF mutation, whereas ERK1 was not able to compensate for loss of ERK2 activity. The...