Irannejadrankouhi Shahryar, Mivehchi Hassan, Eskandari-Yaghbastlo Aisan, Nejati Seyedeh Tabasom, Emrahoglu Sahand, Azarang Fatemeh, Nikroo Abbas, Nabi-Afjadi Mohsen
Faculty of Dentistry, Alborz University of Medical Sciences, Karaj, Iran.
Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
Pharmacol Rep. 2025 Jun 5. doi: 10.1007/s43440-025-00745-2.
Treatment for oral squamous cell carcinoma (OSCC) has seen the rise of receptor tyrosine kinase inhibitors (RTKIs). However, their therapeutic effectiveness is severely limited by the emergence of resistance. Epidermal growth factor receptor (EGFR)-independent survival pathways, extracellular vesicle (EV)-mediated drug sequestration, lysosomal exocytosis, and metabolic reprogramming mediated by METTL1 (methyltransferase-like protein 1) are some of the molecular and cellular mechanisms that underlie RTKI resistance in OSCC. In this line, specific resistance methods are carefully studied, including the signaling processes involving SHP2, the different ways ErbB2 and AKT, and features related to tumor stemness. Additionally, the interaction between resistance and the tumor microenvironment (TME), namely via EVs and modified angiogenic signaling, is emphasized. Novel therapy approaches are put forth to address these issues. The effectiveness of treatment may be improved by combination treatments that include RTKIs with other medications, such as mTOR inhibitors, chemotherapy, radiation, and immunotherapies. Innovative nanotechnology-based strategies, such as exosome-based drug carriers and liposomal drug delivery systems, provide encouraging answers for overcoming resistance and enhancing precise targeting. Furthermore, phytochemicals and herbal remedies are investigated as supplementary approaches to enhance RTKI responses. Despite the potential of these approaches, obstacles, including resolving tumor heterogeneity, limiting off-target effects, and improving delivery methods, continue to be major obstacles to clinical use. To inform personalized medicine strategies, future studies should concentrate on finding predictive biomarkers and conducting thorough preclinical validation. By integrating emerging therapies and addressing these limitations, this work provides a comprehensive foundation for advancing the management of OSCC and improving patient outcomes.
口腔鳞状细胞癌（OSCC）的治疗中，受体酪氨酸激酶抑制剂（RTKIs）日益受到关注。然而，耐药性的出现严重限制了它们的治疗效果。表皮生长因子受体（EGFR）非依赖性生存途径、细胞外囊泡（EV）介导的药物隔离、溶酶体胞吐作用以及由METTL1（甲基转移酶样蛋白1）介导的代谢重编程是OSCC中RTKI耐药性的一些分子和细胞机制。在这方面，人们仔细研究了特定的耐药方法，包括涉及SHP2的信号传导过程、ErbB2和AKT的不同作用方式以及与肿瘤干性相关的特征。此外，还强调了耐药性与肿瘤微环境（TME）之间的相互作用，即通过EVs和修饰的血管生成信号传导。为解决这些问题，人们提出了新的治疗方法。通过将RTKIs与其他药物（如mTOR抑制剂、化疗、放疗和免疫疗法）联合使用的联合治疗，可能会提高治疗效果。基于创新纳米技术的策略，如基于外泌体的药物载体和脂质体药物递送系统，为克服耐药性和增强精准靶向提供了令人鼓舞的解决方案。此外，还研究了植物化学物质和草药疗法作为增强RTKI反应的补充方法。尽管这些方法具有潜力，但包括解决肿瘤异质性、限制脱靶效应和改进给药方法在内的障碍仍然是临床应用的主要障碍。为指导个性化医疗策略，未来的研究应集中于寻找预测性生物标志物并进行全面的临床前验证。通过整合新兴疗法并解决这些局限性，这项工作为推进OSCC的管理和改善患者预后提供了全面的基础。
