Itraconazole targets cell cycle heterogeneity in colorectal cancer.

Simon J.A. Buczacki,Jon Buzzelli,Semiramis Popova,Hayley Francies,Chrysa Koukorava,Louis Vermeulen,Mathew J. Garnett,Douglas J. Winton,Emma Biggs,Lee Hazelwood

doi:10.1084/jem.20171385

Abstract

Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.

Highlights

Colorectal cancer (CRC) is the third most common cancer in the Western World
Human spheroid label–retaining cells are a differentiated population Dormant cells have previously been identified in CRC cell lines and xenografts using dye staining and subsequent dilution assays and are classified as label-retaining cells (LRCs) if the dye is retained with time (Moore et al, 2012)
Significant progress has been made in characterizing the molecular heterogeneity present between tumors, functional heterogeneity is present and will confound both targeted treatments and traditional cytotoxic therapies currently used as adjuvant treatments

Summary

Introduction

CRC is a heterogeneous disease and recent large scale molecular studies have identified clinically relevant overlapping subgroups that can be identified in primary tumors, primary cultures, xenografts, and traditional cell lines (De Sousa E Melo et al, 2013; Guinney et al, 2015; Linnekamp et al, 2018) This intertumoral heterogeneity is a major explanation for differential chemotherapy responses and clinical progression. Dormant CRC cells have been found to be rare, chemoresistant, and yet highly clonogenic, features compatible with a stem cell–like phenotype (Moore et al, 2012; Kreso et al, 2013) Their true molecular identity and the mechanisms underlying dormancy remain elusive, and there is an urgent need to identify compounds that can perturb this dormant state to enable more complete cancer cell killing to prevent late recurrence

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