Hijacking Cellular S-Acylation with Molecular Assemblies Rewires Oncogenic Signaling

In KRAS-mutant PANC-1 cells, the palmitoylated thioester peptide precursor Stb-DPhe-DPhe-SAc (1) increases Golgi-linked assembly, KRAS membrane staining, and ERK/AKT phosphorylation while reducing viability.

• Why it matters: KRAS-mutant cancers are typically targeted by blocking oncogenic signaling, but spatial control over where signaling is perturbed remains a key gap.
• What they did: The authors treated PANC-1 cells with Stb-DPhe-DPhe-SAc (1) and a palmitoylated synthetic form, tracked palmitoylation and Golgi accumulation with a 2-bromopalmitate-sensitive fluorescent analogue, and used palmitoylation inhibition to test dependence.
• The result: Palmitoylation inhibition suppressed Golgi accumulation, attenuated LC3B remodeling, and rescued cell viability, supporting that S-acylation enables organelle-localized molecular assemblies that perturb KRAS localization and stress signaling.

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