Hijacking Cellular S-Acylation with Molecular Assemblies Rewires Oncogenic Signaling

This preprint describes a thioester peptide precursor that is palmitoylated in cells, assembles at the Golgi, and increases plasma-membrane-associated KRAS staining with higher ERK and AKT phosphorylation, while still reducing PANC-1 viability. The proposed mechanism is spatial perturbation of KRAS localisation through endogenous lipidation machinery rather than suppression of KRAS signalling. Claidex holds three KRAS failures: bgb-53038-kras-solid-tumors-phase1-strategic-reprioritization, sotorasib-durvalumab-kras-g12c-ctdna-stage3-nsclc-phase2-enrollment-collapse, and opnurasib-kras-g12c-combination-platform-kontrast-03-phase1-2-termination. None of the three failed on efficacy grounds, so the KRAS inhibition thesis is not what those records contradict. The preprint matters because it inverts the usual pharmacodynamic readout, with increased pathway phosphorylation accompanying reduced viability. Any KRAS programme using ERK suppression as its proximal activity marker should note that the relationship between that marker and cell killing is not fixed. Severity is MODERATE on three prior failures.