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

• 成果类型: Article
• 署名作者: Valcikova, Barbora; Vadovicova, Natalia; Smolkova, Karolina; Zacpalova, Magdalena; Krejci, Pavel; Lee, Shannon; Rauch, Jens; Kolch, Walter; von Kriegsheim, Alexander; Dorotikova, Anna; Andrysik, Zdenek; Vichova, Rachel; Vacek, Ondrej; Soucek, Karel; Uldrijan, Stjepan
• 署名单位: Masaryk University; St. Anne's University Hospital Brno (FNUSA); St. Anne's University Hospital Brno (FNUSA-ICRC); Czech Academy of Sciences; Institute of Animal Physiology & Genetics of the Czech Academy of Sciences; University College Dublin; University College Dublin; University College Dublin; University of Edinburgh; University of Colorado System; University of Colorado Anschutz Medical Campus; Czech Academy of Sciences; Institute of Biophysics of the Czech Academy of Sciences; Masaryk University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10640
• DOI: 10.1073/pnas.2321305121
• 发表日期: 2024-10-29
• 关键词: initiation-factor 4e; kinase phosphatases; feedback inhibition; mek; phosphorylation; PATHWAY; resistance; mnk1; addiction; GROWTH

摘要

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- na & iuml;ve 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.