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, statininduced 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. Mol Cancer Ther; 13(11); 2559-71. Ó2014 AACR.

Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

“…Normal mammary tissues or areas containing tumor were identified by gross pathologic examinations. Approximately 2 mm cores were obtained using a sterile biopsy punch that was further sliced with a scalpel to obtain approximately 2 × 1 mm tumor slices (Dayekh et al ., ; Sulaiman et al ., ). The slices were randomized, and three slices were placed into each well of 24‐well plate and cultured in DMEM‐F12 medium supplemented with 10% FBS, 1% penicillin/streptomycin, 1 μg·mL −1 insulin, 0.5 ng·mL −1 hydrocortisol, and 3 ng·mL −1 epidermal growth factor.…”

Efeitos in vitro das estatinas em câncer de cabeça e pescoço

“…However, when a combination of gefitinib and lovastatin was tested in SCC9 cells, cell death was enhanced by more than 90% when compared to each drug alone [8,11]. The same results were found by Dayekh et al [23] when used lovastatin combined with monensin and erlotinib. Llobet et al, in 2014, [26] showed that simvastatin might enhance antitumor response when in combination with radiation and cetuximab.…”

“…The studies were published from 2001 to 2014, and all of them were in English. They were conducted in five different countries: Canada [6,8,9,11,[20][21][22][23], France [24], Germany [25], Spain [26] and the United States of America [7,27,28]. All of the selected studies were in vitro [6-9, 11, 20-27]; however, three of them also involved in vivo experiments [7,25,26].…”

“…Dayekh et al, [23] used monensin, lovastatin and erlotinib alone and in combination to treat SCC9, SCC25 and GM-38 (normal lung fibroblasts) cells. They confirmed the ability of monensin to potentiate the cytotoxicity of erlotinib and lovastatin and showed that combination of 5µmol/L of monensin with 10µmol/L erotinib for 24 hours have 38.7% of apoptosis in SCC25 cells.…”

“…These in vitro studies supported the idea that statins have potential as a therapy for HNSCC. To evaluate the effect of statins on HNSCC cells, all the authors that used MTT assays or trypan blue assays [8,11,[20][21][22][23][24][25] demonstrated that statins alone could effectively and dose dependently kill more than 50% of the cells and inhibit proliferation ( Table 2). The effect of statins on HNSCC cells was also evaluated in combination with radiation [25] or with other chemotherapeutics (cisplatin, 5-fluorouracil, paclitaxel, carboplatin, and oxaplatin) [21], but in these cases, the statins had no significant differences.…”