eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
Year: 2024
Type: article
Abstract: The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
Authors: Barbora Valcikova, Natalia Vadovicova, Karolina Smolkova, Magdalena Zacpalova, Pavel Krejci, Shannon Lee, Jens Rauch, Walter Kolch, Alexander von Kriegsheim, Anna Dorotikova, Zdenek Andrysik, Rachel Vichova, Ondrej Vacek, Karel Soucek, Stjepan Uldrijan
Institutions: Masaryk University, International Clinical Research Center, St. Anne's University Hospital Brno, Czech Academy of Sciences, Institute of Animal Physiology and Genetics, University College Dublin, Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, University of Colorado Anschutz, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Biophysics
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G1005326806, G176604203, G2039240949, G2270135567, Precision Oncology Ireland, Circulating tumor cells as a preclinical tool for analysis of cancer heterogeneity and therapy response, G310317919, High resolution metabolite and peptide mass spectrometry, G5508342132, G5919731826, G7363506711, New molecular mechanisms in the dynamic control of the ERK pathway in melanoma as potential therapeutic targets, G9000118262
OpenAlex ID: W4403638545