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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Combinational Inhibition of the eIF4F Complex, AKT1, and EZH2 Enhances Anticancer Effects in BRAFV600E Mutant A375

Yuanxin Miao1,2, Fengyun Hao3, Sae Hwi Ki1,4

  • 1Department of Plastic and Reconstructive Surgery, Inha University School of Medicine, Incheon, 22332, Republic of Korea.

Oncology Research
|March 9, 2026
PubMed
Abstract

Insights

Eukaryotic initiation factor 4F inhibitors cause resistance in BRAF-mutant melanoma by reactivating ERK1/2 and AKT1 pathways. Combining these inhibitors with EZH2 and AKT1 inhibitors overcomes this resistance, improving treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Eukaryotic initiation factor 4F (eIF4F) translation initiation complex inhibitors (eIF4Fi) can paradoxically hyperactivate extracellular signal-regulated kinases 1/2 (ERK1/2).
  • This hyperactivation contributes to acquired resistance to BRAF inhibitors in melanoma, posing a significant clinical challenge.

Purpose of the Study:

  • To investigate mechanisms for overcoming eIF4Fi resistance in BRAFV600E mutant melanoma cells.
  • To explore the underlying molecular pathways involved in this resistance and identify potential therapeutic strategies.

Main Methods:

  • Melanoma cells (sensitive A375 and resistant A375R) were treated with eIF4Fi RocA in vitro.
  • Impact of RocA on ERK1/2, AKT1, eIF4E, and EZH2 activity, as well as apoptotic and proliferative proteins, was assessed.
  • Combined effects of eIF4Fi, AKT1 inhibitor, EZH2 inhibitor, and vemurafenib on tumor growth were evaluated in vitro and in vivo.

Main Results:

  • RocA inhibited proliferation and induced apoptosis in sensitive cells, but only inhibited proliferation in resistant cells.
  • RocA rapidly reactivated ERK1/2, followed by delayed activation of eIF4E and AKT1.
  • ERK1/2 positively regulated EZH2, while AKT1 influenced expression of multiple proteins including c-Myc, c-Jun, and BMF; RocA downregulated bcl-2 and Mcl-1.
  • Combined AKT1 inhibitor and eIF4Fi enhanced apoptosis, while EZH2 inhibitor reduced proliferation.

Conclusions:

  • The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling, leading to resistance to both eIF4Fi and BRAF inhibitors.
  • Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively overcomes resistance to both eIF4F complex and BRAF inhibitors, offering a promising therapeutic approach.
Keywords:
AKT serine/threonine kinase 1B-raf proto-oncogene serine/threonine kinase-inhibitorBcl-2 modifying factorMelanomaenhancer of zeste homolog 2eukaryotic initiation factor 4F complex inhibitorextracellular signal-regulated kinases 1/2

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