Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer by Suppressing the HER2/AKT Signaling Pathway

Wei Zhang, Ankur S. Bhagwath, Zeeshan Ramzan, Taylor A. Williams, Indhumathy Subramaniyan, Vindhya Edpuganti, Raja Reddy Kallem, Kerry B. Dunbar, Peiguo Ding, Ke Gong, Samuel A. Geurkink, Muhammad S Beg, James Kim, Qiuyang Zhang, Amyn A Habib, Sung Hee Choi, Ritu Lapsiwala, Gayathri Bhagwath, Jonathan E. Dowell, Shelby D. MeltonChunfa Jie, William C. Putnam, Thai H Pham, David H. Wang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1904-1915
Number of pages12
JournalMolecular Cancer Therapeutics
Volume20
Issue number10
DOIs
StatePublished - Oct 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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