A Novel D-peptide modulates DCLK1 Gelsolin interactions, reducing PDAC tumor growth

TL;DR

A new D-peptide targets a specific part of DCLK1, reducing pancreatic cancer growth without killing cells.

Contribution

A novel D-peptide is developed to modulate DCLK1 isoform 4 interactions, offering a new therapeutic strategy for PDAC.

Findings

D-peptides selectively target DCLK1 isoform 4's extracellular domain, suppressing PDAC cell proliferation.

D-peptides reduce tumor growth in xenograft models by modulating DCLK1 interactions with pro-tumorigenic proteins like plasma gelsolin.

The study highlights non-kinase functions of DCLK1 as a potential therapeutic target in PDAC.

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. Isoform 4, which lacks microtubule-binding domains but contains a unique extracellular domain (ECD), 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.

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