Affiliation:
1. Department of Oncology, Huanggang Central Hospital of Yangtze University, Huanggang
2. Department of Otorhinolaryngology & Head and Neck Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
Abstract
Improving the clinical management of nasopharyngeal carcinoma (NPC) is an unmet need owing to the high incidence of treatment failure caused by radioresistance. In our study, we observed increased phosphorylation of translation initiation factor 4E (eIF4E), regulated by MAP kinase-interacting kinase (MNK), in NPC cells following irradiation treatment. Using siRNA to deplete MNK, we found that radiation-induced eIF4E phosphorylation was eliminated, NPC cell sensitivity to radiation was enhanced, and radioresistant NPC cell viability was reduced. Furthermore, we tested three pharmacological MNK inhibitors (eFT508, CGP57380, and cercosporamide) and found that they were effective against radioresistant NPC cells and synergized with irradiation. In-vivo experiments confirmed that eFT508, at a tolerable dose, inhibited the growth of radioresistant NPC and synergized with radiation in a radiosensitive NPC xenograft model. Our research highlights the activation of MNK-mediated survival mechanisms in NPC in response to radiotherapy and the potential of combining radiation with MNK inhibitors as a sensitizing strategy. Notably, eFT508 is currently being investigated in clinical trials for cancer treatment, and our findings may prompt the initiation of clinical trials using eFT508 in radioresistant NPC patients.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cancer Research,Pharmacology (medical),Pharmacology,Oncology
Reference25 articles.
1. The evolving epidemiology of nasopharyngeal carcinoma.;Chang;Cancer Epidemiol Biomarkers Prev,2021
2. Nasopharyngeal carcinoma: an evolving paradigm.;Wong;Nat Rev Clin Oncol,2021
3. Nasopharyngeal carcinoma: clinical achievements and considerations among treatment options.;Liu;Front Oncol,6357
4. Multiple mechanisms involving in radioresistance of nasopharyngeal carcinoma.;Zhan;J Cancer,2020
5. Dissecting eIF4E action in tumorigenesis.;Wendel;Genes Dev,2007