Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis

Cristina Morales Torres,Elanor N Wainwright,Michael Bustin,Steven Howell,William Grey,Charles Swanton,Matthew J Martin,Sebastijan Hobor,Michael Howell,Dominique Bonnet,Paola Scaffidi,Eva Grönroos,Paul D Smith,Harshil Patel,Mary Y Wu,Ambrosius P Snijders,Joana Carvalho

doi:10.1038/s41467-020-15615-z

Abstract

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.

Highlights

IntroductionTargeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging
Continuous cancer growth is driven by subsets of self-renewing malignant cells
We show that multiple HDAC inhibitors (HDACi) restore high levels of H1.0 in a large panel of cell lines from numerous cancer types and in patient-derived xenografts (PDXs)

Summary

Introduction

Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Quisinostat hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. The differentiation process that naturally occurs during cancer growth inhibits self-renewal of tumor cells and effectively deprives them of malignant properties. We demonstrate that Quisinostat, a potent second-generation HDACi17, inhibits cancer cell self-renewal, effectively halting disease maintenance and relapse. Identification of a well-tolerated compound as a specific inhibitor of cancer cell self-renewal and characterization of its mechanism of action provide a means to induce a durable response in patients without causing severe side effects

Methods

Results

Conclusion