@article{74ee659d7499424080747a2fe434783b,
title = "Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer by Suppressing the HER2/AKT Signaling Pathway",
abstract = "Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro. Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.",
author = "Wei Zhang and Bhagwath, {Ankur S.} and Zeeshan Ramzan and Williams, {Taylor A.} and Indhumathy Subramaniyan and Vindhya Edpuganti and Kallem, {Raja Reddy} and Dunbar, {Kerry B.} and Peiguo Ding and Ke Gong and Geurkink, {Samuel A.} and Beg, {Muhammad S.} and James Kim and Qiuyang Zhang and Habib, {Amyn A.} and Choi, {Sung Hee} and Ritu Lapsiwala and Gayathri Bhagwath and Dowell, {Jonathan E.} and Melton, {Shelby D.} and Chunfa Jie and Putnam, {William C.} and Pham, {Thai H.} and Wang, {David H.}",
note = "Funding Information: We thank Sanjai Sabu, Jessica Vallejo, Pooja Dalal, and Mary Mason for regulatory, clinical coordination, and patient data management assistance. This work was supported by a New Investigator Award (to W. Zhang) from the VA North Texas Health Care System, the U.S. Department of Veterans Affairs 5I01CX001668 (to K.B. Dunbar) and 2I01BX002559–07 (to A.A. Habib); the NIH 1R01CA196851 (to J. Kim), 1R01CA244212–01A1 (to A.A. Habib) and R01-DK97340 (to D.H. Wang), the Cancer Prevention Research Institute of Texas Core Facilities Support Award RP170003 (to W.C. Putnam), the American Cancer Society ACS-RSG-16–090–01-TBG (to J. Kim), and the Friends of the Simmons Comprehensive Cancer Center (to D.H. Wang). Funding Information: K.B. Dunbar reports grants from Department of Veterans Affairs VA MERIT CSR&D during the conduct of the study; grants from Ironwood Pharmaceuticals outside the submitted work. M.S. Beg reports personal fees from Ipsen, Merck, AZ, FMI, outside the submitted work. J. Kim reports grants from NCI and grants from American Cancer Society during the conduct of the study; personal fees from COTA Inc outside the submitted work. J.E. Dowell reports personal fees from Astra Zeneca during the conduct of the study; personal fees from Physicians Education Resource outside the submitted work. W.C. Putnam reports grants from Cancer Prevention & Research Institute of Texas during the conduct of the study. D.H. Wang reports grants from US NIDDK and grants from Friends of the Simmons Comprehensive Cancer Center during the conduct of the study. No disclosures were reported by the other authors. Funding Information: We thank Sanjai Sabu, Jessica Vallejo, Pooja Dalal, and Mary Mason for regulatory, clinical coordination, and patient data management assistance. This work was supported by a New Investigator Award (to W. Zhang) from the VA North Texas Health Care System, the U.S. Department of Veterans Affairs 5I01CX001668 (to K.B. Dunbar) and 2I01BX002559?07 (to A.A. Habib); the NIH 1R01CA196851 (to J. Kim), 1R01CA244212?01A1 (to A.A. Habib) and R01-DK97340 (to D.H. Wang), the Cancer Prevention Research Institute of Texas Core Facilities Support Award RP170003 (to W.C. Putnam), the American Cancer Society ACS-RSG-16?090?01TBG (to J. Kim), and the Friends of the Simmons Comprehensive Cancer Center (to D.H. Wang). Publisher Copyright: {\textcopyright}2021 The Authors; Published by the American Association for Cancer Research",
year = "2021",
month = oct,
doi = "10.1158/1535-7163.MCT-20-0638",
language = "English (US)",
volume = "20",
pages = "1904--1915",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}