# Targeting the TLK1-MK5 Axis Suppresses Prostate Cancer Metastasis

## TL;DR

Blocking the TLK1-MK5 pathway in prostate cancer cells reduces metastasis and could lead to new treatments.

## Contribution

The study identifies the TLK1-MK5 axis as a novel target for suppressing prostate cancer metastasis.

## Key findings

- Disrupting the TLK1-MK5 axis curtails metastatic spread in PC3 cells and age-related metastases in a mouse model.
- Two drugs targeting TLK1 and MK5 are safe and effective in preclinical and early clinical trials.

## Abstract

We demonstrate with pharmacological and genetic approaches that by targeting the TLK1>MK5 nexus it was possible to strongly curtail the spread of metastatic, AR-independent PC3 cells and age-related metastases in a TRAMP/MK5-KO model. Importantly, one targeting drug (GLPG—MK5i) has been proven safe in Phase I clinical trials for the treatment of arthritis, while the other (J54—TLKi) is now commercially available and was shown to have no significant behavioral or fitness side effects.

Background: The spread of metastatic prostate cancer (PCa) is responsible for the majority of PCa-related deaths, yet the precise mechanisms driving this process remain unclear. We have identified a novel interaction between two distinct promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), which triggers a signaling cascade that promotes metastasis. In PCa, the TLK1-MK5 pathway may play a critical role, as androgen deprivation therapy (ADT) has been linked to increased expression of both TLK1 and MK5 in metastatic patients linked with poor survival. Objectives: In this study, we directly examined the effects of disrupting the TLK1>MK5 axis on the motility, invasiveness, and metastatic potential of PCa cells. Methods: To establish this, we used both pharmacologic and systemic approaches with genetically engineered mouse models and the use of IVIS. Results: The results of targeting the TLK1>MK5 axis support the notion that this axis is essential for the spread of metastatic cells and the development of age-related metastases.