Musashi inhibitor Ro 08–2750 attenuates triple-negative breast cancer cell proliferation and migration and acts as a novel chemo- and radiosensitizer

Abstract

Introduction

The Musashi RNA-binding proteins contribute to proliferation, stemness, and therapy resistance in triple-negative breast cancer (TNBC) and have been associated with reduced overall survival in patients.

Objectives

Leveraging the availability of a Musashi inhibitor, Ro 08–2750, we here aimed to assess the therapeutic potential of Musashi protein inhibition in TNBC.

Methods

Cell proliferation and clonogenic survival were quantified at different concentrations of the inhibitor in primary, patient-derived breast cancer cultures as well as established TNBC cell lines. Flow cytometry, spheroid formation, MTT assays and digital holographic microscopy were used to assess inhibitor-induced functional effects, while RNA sequencing, dot blot and western blot assays confirmed gene expression changes.

Results

Ro 08–2750 affects cell proliferation and survival in a dose-dependent manner by upregulating apoptosis and inducing a cell cycle arrest. Cell migration was reduced as stemness markers were downregulated. Inhibitor treatment also increased DNA double strand breaks after downregulation of Musashi-associated DNA repair mechanisms. Accordingly, Ro 08–2750 acted as a radio- and chemosensitizer in combined treatment applications. Gene expression findings were consistent with observed functional changes.

Conclusion

Our results indicate that Musashi protein inhibition may attenuate tumor progression and sensitize cells to conventional breast cancer therapy, underlining the therapeutic potential of this approach.