Itraconazole targets cell cycle heterogeneity in colorectal cancer.

The Journal of Experimental Medicine
Simon J A BuczackiDouglas J Winton

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.

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Citations

Dec 30, 2018·The Journal of Experimental Medicine·Dong RenLibing Song
Jul 10, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Jinhua ZhangHong Zhang
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Methods Mentioned

BETA
xenografts
FACS
transcriptomic
RNAseq
xenograft
Fluorescence
flow cytometry
transgenic
transfection
dissection

Software Mentioned

GraphPad
GSEA
Matlab
fminsearch
BWA
Pindel
Prism
MEM
Excel
CaVEMan

Related Concepts

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