# Impact of Mutational Status on Intracellular Effects of Cell‐Permeable CaaX Peptides in Pancreatic Cancer Cells

## TL;DR

This study explores how cell-permeable CaaX peptides affect pancreatic cancer cells, particularly those with KRas mutations, by interfering with prenylation and altering signaling pathways.

## Contribution

The study reveals that CaaX peptides specifically alter KRas signaling and membrane localization in mutated pancreatic cancer cells.

## Key findings

- CaaX peptides alter KRas plasma membrane localization in PANC-1 cells, likely due to disturbed prenylation.
- KRas signaling is impacted differently in mutated PANC-1 cells compared to wildtype BxPC-3 cells.
- CaaX peptides affect KRas-dependent regulators like NF1 and SOS1 in mutated cells.

## Abstract

Prenyltransferases add a lipid group to the cysteine of a CaaX motif of proteins. This posttranslational modification enables proteins to attach to membranes where they are essential hubs for signaling, trafficking, and apoptosis. Recently, cell‐permeable CaaX‐peptides are developed as possible tools to interfere with the prenylation machinery. These peptides cause cytotoxic effects, particularly in KRas mutant pancreatic cancer cells (PANC‐1) in which they also alter downstream signaling of Ras proteins. Herein, the aim is to get more clues about the relevance of the mutational status of KRas. Therefore, the activity of CaaX‐peptides in KRas wildtype BxPC‐3 and KRas mutated PANC‐1 cells is compared. CaaX‐peptides differently influence these two cell lines, although they internalize pretty much to the same extent. Indeed, an altered KRas plasma membrane localization in PANC‐1 cells is observed, probably induced by disturbed KRas prenylation based on the presence of CaaX‐peptides. The impact of CaaX‐peptides on KRas signaling is likely dependent on the KRas mutation in PANC‐1 cells in which they further trigger effects on KRas‐dependent regulators, e.g., Neurofibromin −1 (NF1) and son of sevenless homolog 1 (SOS1). All in all, CaaX peptides are identified as promising tools for studying and manipulating the function of therapeutically important prenylated proteins.

This work deals with intracellular effects of cell‐permeable CaaX‐peptides, designed to influence prenylated proteins like KRas. The results show that after CaaX‐1 treatment, not only KRas expression and signaling are specifically altered in mutated pancreatic cancer cells, but also plasma membrane localization of KRas is affected. Thus, CaaX‐peptides are promising tools to manipulate prenylation‐dependent proteins.© 2025 WILEY‐VCH GmbH