TY - JOUR
T1 - Itraconazole targets cell cycle heterogeneity in colorectal cancer
AU - Buczacki, Simon J. A.
AU - Popova, Semiramis
AU - Biggs, Emma
AU - Koukorava, Chrysa
AU - Buzzelli, Jon
AU - Vermeulen, Louis
AU - Hazelwood, Lee
AU - Francies, Hayley
AU - Garnett, Mathew J.
AU - Winton, Douglas J.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052624889&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29853607
U2 - https://doi.org/10.1084/jem.20171385
DO - https://doi.org/10.1084/jem.20171385
M3 - Article
C2 - 29853607
SN - 0022-1007
VL - 215
SP - 1891
EP - 1912
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -