A novel D-peptide modulates DCLK1 gelsolin interactions, reducing PDAC tumor growth

TL;DR

A new D-peptide targets DCLK1 to reduce pancreatic cancer growth by disrupting harmful protein interactions.

Contribution

A novel D-peptide is introduced that modulates DCLK1-gelsolin interactions to inhibit PDAC tumor progression.

Findings

D-peptides selectively target the DCLK1 ECD and suppress PDAC cell proliferation in vitro.

DCLK1 isoform 4 interacts with pro-tumorigenic proteins like plasma gelsolin, which is modulated by D-peptides.

D-peptide treatment reduces tumor growth in xenograft models without inducing cell death.

Abstract

What drives inflammation-associated tumorigenesis and progression in pancreatic ductal adenocarcinoma (PDAC)? Doublecortin-like kinase 1 (DCLK1) is a central driver of inflammation-associated tumorigenesis, with elevated expression linked to worse clinical outcomes. Two isoforms of DCLK1 possess a unique extracellular domain (ECD). DCLK1 isoform 2 contains two microtubule-binding domains, while isoform 4, lacks the microtubule-binding domains but, plays a pivotal role in tumor progression. We identified novel D-peptides that selectively target this ECD, significantly suppressing PDAC cell proliferation in vitro and tumor growth in xenograft models without inducing cell death. In silico modeling and binding assays revealed DCLK1 isoform 4 interacts with pro-tumorigenic proteins like plasma gelsolin (pGSN), with D-peptides modulating these interactions. These findings underscore DCLK1’s non-kinase functions as a therapeutic target and highlight novel avenues for developing precision treatments aimed at halting cancer progression and improving patient outcomes.

The online version contains supplementary material available at 10.1038/s41598-025-19722-z.

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