title: Monensin inhibits epidermal growth factor receptor trafficking and activation: synergistic cytotoxicity in combination with EGFR inhibitors.
abstract: Targeting the EGFR, with inhibitors such as erlotinib, represents a promising therapeutic option in advanced head and neck squamous cell carcinomas (HNSCC). However, they lack significant efficacy as single agents. Recently, we identified the ability of statins to induce synergistic cytotoxicity in HNSCC cells through targeting the activation and trafficking of the EGFR. However, in a phase I trial of rosuvastatin and erlotinib, statin-induced muscle pathology limited the usefulness of this approach. To overcome these toxicity limitations, we sought to uncover other potential combinations using a 1,200 compound screen of FDA-approved drugs. We identified monensin, a coccidial antibiotic, as synergistically enhancing the cytotoxicity of erlotinib in two cell line models of HNSCC, SCC9 and SCC25. Monensin treatment mimicked the inhibitory effects of statins on EGFR activation and downstream signaling. RNA-seq analysis of monensin-treated SCC25 cells demonstrated a wide array of cholesterol and lipid synthesis genes upregulated by this treatment similar to statin treatment. However, this pattern was not recapitulated in SCC9 cells as monensin specifically induced the expression of activation of transcription factor (ATF) 3, a key regulator of statin-induced apoptosis. This differential response was also demonstrated in monensin-treated ex vivo surgical tissues in which HMG-CoA reductase expression and ATF3 were either not induced, induced singly, or both induced together in a cohort of 10 patient samples, including four HNSCC. These results suggest the potential clinical utility of combining monensin with erlotinib in patients with HNSCC.
authors.affiliation: Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine and the Department of Biochemistry, The University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Khalil
authors.initials: K
authors.lastname: Dayekh
authors.affiliation: Department of Otolaryngology, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johnson-Obaseki
authors.affiliation: Department of Otolaryngology, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Corsten
authors.affiliation: Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada. Department of Thoracic Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Villeneuve
authors.affiliation: Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Harmanjatinder S
authors.initials: HS
authors.lastname: Sekhon
authors.affiliation: Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada. Department of Gynaecologic Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Johanne I
authors.initials: JI
authors.lastname: Weberpals
authors.affiliation: Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine and the Department of Biochemistry, The University of Ottawa, Ottawa, Ontario, Canada. jdimitroulakos@ohri.ca.
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008985:Monensin / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D008985:Monensin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors