Differential dependency of BRAF-mutant melanoma on ERK2 versus ERK1

To elucidate the relative contributions of ERK1 and ERK2 in BRAFV600mut melanoma, we analyzed data from three independent genetic dependency screens performed in large panels of cancer cell lines. Despite the high homology between ERK1 and ERK2, melanoma cell lines were dependent on ERK2 but not ERK1. We validated these findings with genetic and pharmacologic loss-of-function and rescue experiments and found that overexpressed ERK1 could compensate for ERK2 suppression. Furthermore, both ERK1 and ERK2 required the FRS but not the DRS to mediate viability. We analyzed transcriptomic and proteomic data sets across large cancer cell line panels and found that ERK2 is relatively overexpressed in melanoma cells compared to ERK1 and compared to other cancer types, and ERK2 dependency correlates with mRNA or protein expression across all cell types. Finally, we analyzed signaling changes upon ERK1 and ERK2 suppression in two ERK2-dependent BRAFV600mut cell lines and found that ERK2 is the primary isoform driving MAPK signaling and transcriptional programing in these cells.