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Updated: May 15, 2026

Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease
06:25

Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease

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ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E

Xijie Yang1, Xi Qiao1, Sarah Schmidt1

  • 1Department of Medicine, Huddinge, Karolinska Institutet, Huddinge SE-141 83, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|May 13, 2026
PubMed

Insights

Isoprenylcysteine carboxyl methyltransferase (ICMT) inhibition suppresses BRAFV600E melanoma growth by targeting INPP5E. This ICMT-INPP5E axis is crucial for BRAFV600E-driven tumor progression and resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Isoprenylcysteine carboxyl methyltransferase (ICMT) methylates prenylated CAAX proteins, impacting cell signaling.
  • The role of ICMT in BRAFV600E-mutant cancers and its substrates are not fully understood.

Purpose of the Study:

  • To investigate the role of ICMT in BRAFV600E-driven melanoma.
  • To identify critical ICMT substrates and elucidate the underlying mechanisms.

Main Methods:

  • Genetic and pharmacologic inhibition of ICMT (UCM-1336).
  • Cell proliferation, invasion, and tumor growth assays in melanoma models.
  • Identification and functional analysis of ICMT substrates, including INPP5E.

Main Results:

  • ICMT inhibition suppressed proliferation and invasion in BRAFV600E melanoma cells and reduced tumor growth.
  • ICMT inhibition also affected BRAF-inhibitor-resistant melanoma cells.
  • INPP5E was identified as an ICMT-dependent substrate, with its reduced methylation and membrane displacement leading to increased PI(4,5)P2 levels.

Conclusions:

  • An ICMT-INPP5E signaling axis supports BRAFV600E-driven tumor growth.
  • Targeting ICMT may be a viable strategy for treating BRAFV600E-mutant melanoma, including resistant forms.
Keywords:
BRAFV600E-driven cancerCAAX protein processingICMTINPP5E

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