eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

The eIF4F transla􀆟on ini􀆟a􀆟on complex plays a cri􀆟cal role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel func􀆟on of eIF4F in the nega􀆟ve regula􀆟on of the RAS/RAF/MEK/ERK mitogen-ac􀆟vated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essen􀆟al for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS muta􀆟ons. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a nega􀆟ve feedback regulator of ERK ac􀆟vity, requires con􀆟nuous produc􀆟on in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS muta􀆟ons. Treatment with small molecule eIF4F inhibitors
disrupts the nega􀆟ve feedback control of MAPK signaling, leading to ERK hyperac􀆟va􀆟on and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quan􀆟ta􀆟ve analyses reveal a high spare signaling capacity in the ERK pathway, sugges􀆟ng that eIF4F-dependent feedback keeps the majority of ERK molecules inac􀆟ve under normal condi􀆟ons. Overall, our findings highlight the crucial role of eIF4F in regula􀆟ng ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the nega􀆟ve feedback control of MAPK ac􀆟vity in melanomas with BRAF and NRAS ac􀆟va􀆟ng muta􀆟ons.