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J Exp Med. 2018 Jul 2;215(7):1891-1912. doi: 10.1084/jem.20171385. Epub 2018 May 31.

Itraconazole targets cell cycle heterogeneity in colorectal cancer.

Author information

1
Cancer Research UK (CRUK) Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, England, UK simon.buczacki@cruk.cam.ac.uk.
2
Cancer Research UK (CRUK) Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, England, UK.
3
Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology (OIRO), Department of Oncology, University of Oxford, Oxford, UK.
4
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
5
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, England, UK.
6
Cancer Research UK (CRUK) Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, England, UK doug.winton@cruk.cam.ac.uk.

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.

PMID:
29853607
PMCID:
PMC6028508
DOI:
10.1084/jem.20171385
[Indexed for MEDLINE]
Free PMC Article

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