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

• Published in: Molecular cancer therapeutics 2021-10, Vol.20 (10), p.1904-1915
• Main Authors: Zhang, Wei, Bhagwath, Ankur S, Ramzan, Zeeshan, Williams, Taylor A, Subramaniyan, Indhumathy, Edpuganti, Vindhya, Kallem, Raja Reddy, Dunbar, Kerry B, Ding, Peiguo, Gong, Ke, Geurkink, Samuel A, Beg, Muhammad S, Kim, James, Zhang, Qiuyang, Habib, Amyn A, Choi, Sung-Hee, Lapsiwala, Ritu, Bhagwath, Gayathri, Dowell, Jonathan E, Melton, Shelby D, Jie, Chunfa, Putnam, William C, Pham, Thai H, Wang, David H
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Cycle; Cell Movement; Cell Proliferation; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Itraconazole - pharmacokinetics; Itraconazole - pharmacology; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Mice, Nude; Prognosis; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Receptor, ErbB-2 - antagonists & inhibitors; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0638

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 G -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 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.