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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.

Original publication

DOI

10.1084/jem.20171385

Type

Journal article

Journal

J Exp Med

Publication Date

02/07/2018

Volume

215

Pages

1891 - 1912

Keywords

Animals, Cell Cycle, Cell Cycle Checkpoints, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cell Separation, Cellular Senescence, Colorectal Neoplasms, Humans, Itraconazole, Mice, Neoplastic Stem Cells, Organoids, Phenotype, Receptors, G-Protein-Coupled, Spheroids, Cellular, Staining and Labeling, Wnt Signaling Pathway