370: ICMT and INPP5E enable BRAFV600E tumor growth

Yang X et al., Proceedings of the National Academy of Sciences - Genetic and pharmacologic inhibition of ICMT suppresses proliferation, invasion, and tumor growth in BRAFV600E-driven models and identifies INPP5E as an ICMT-dependent CAAX substrate whose membrane targeting supports melanoma growth. Key terms: ICMT, INPP5E, BRAFV600E, melanoma, UCM-1336.

Study Highlights:
ICMT genetic knockdown or pharmacologic inhibition (UCM-1336) reduced proliferation and invasion of BRAFV600E-mutant melanoma cells, decreased tumor growth in xenografts and mouse models, and retained activity in BRAF-inhibitor-resistant cells. ICMT inhibition reduced INPP5E carboxyl methylation, displaced INPP5E from membranes to the cytosol, and increased cellular PI(4,5)P2. Forced membrane targeting of INPP5E (Lyn-INPP5E) partially rescued proliferation and tumor growth during ICMT suppression. These results implicate an ICMT–INPP5E axis that supports BRAFV600E-driven tumor growth without measurable suppression of MAPK signaling.

Conclusion:
ICMT-dependent methylation and membrane targeting of INPP5E contribute to BRAFV600E-driven tumor growth, and ICMT inhibition (genetic or with UCM-1336) impairs melanoma growth including in BRAF-inhibitor-resistant models, highlighting ICMT as a context-dependent therapeutic vulnerability.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
ICMT supports BRAF
V600E
-driven tumor growth by membrane targeting of the CAAX protein INPP5E

First author:
Yang X

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2601795123

Reference:
Yang X, Qiao X, Schmidt S, et al. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. PNAS. 2026;123(20):e2601795123. doi:10.1073/pnas.2601795123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/icmt-inpp5e-brafv600e-membrane-targeting

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing ICMT/CAAX processing, INPP5E as an ICMT substrate, membrane targeting and PI(4,5)P2 effects, rescue experiments, in vitro/in vivo models, and therapeutic implications.
- transcript topics: ICMT and CAAX protein processing; INPP5E as an ICMT substrate and its membrane localization; Impact of ICMT inhibition on BRAFV600E melanoma cell proliferation and invasion; MAPK signaling independence from ICMT inhibition; In vivo models and genetic/pharmacologic ICMT suppression; Rescue experiments with Lyn-INPP5E and rescue implications

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ICMT inhibition reduces BRAFV600E-driven melanoma cell proliferation and invasion in vitro and tumor growth in vivo.
- INPP5E is an ICMT-dependent CAAX substrate; ICMT inhibition reduces INPP5E methylation and displaces it from membranes.
- Displacement of INPP5E increases plasma membrane PI(4,5)P2, disrupting signaling and contributing to tumor cell death.
- Forced membrane targeting of INPP5E (LYN-INPP5E) partially rescues proliferation and tumor growth during ICMT suppression.
- Nontransformed fibroblasts show less sensitivity to ICMT inhibition, indicating a therapeutic window.
- MEK/ERK phosphorylation is not reduced by ICMT inhibition, indicating a MAPK-independent mechanism.

QC result: Pass.