Imani Saber, Roozitalab Ghazaal, Emadi Mahdieh, Moradi Atefeh, Behzadi Payam, Jabbarzadeh Kaboli Parham
Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, China.
Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
Front Oncol. 2024 Nov 8;14:1504142. doi: 10.3389/fonc.2024.1504142. eCollection 2024.
Melanoma, a highly aggressive form of skin cancer, poses a significant global health burden, with 331,647 new cases and 58,645 deaths reported in 2022. The development of melanoma is influenced by various factors, including sunlight exposure and BRAF mutations that activate the MAPK/ERK pathway. The introduction of BRAF and MEK inhibitors has revolutionized the treatment landscape for melanoma patients. However, innate and acquired therapeutic resistance remains a significant challenge. This review provides a comprehensive overview of the current state of BRAF-targeted therapies in melanoma, highlighting the efficacy and limitations of FDA-approved combinations of BRAF and MEK inhibitors such as vemurafenib, dabrafenib, trametinib, and cobimetinib. The review also explores the off-target effects of BRAF inhibitors on endothelial cells, emphasizing the need for more selective therapies to minimize vascular complications and metastatic potential. The article also discusses potential druggable targets, including ERK5, CD73, ALDH1A1, PLA1A, and DMKN, which are promising in addressing diagnostic hurdles and guiding personalized therapeutic decisions. Recent studies on regorafenib, ERK5 signaling, and CD73 inhibition are highlighted as novel strategies to overcome resistance and improve treatment outcomes. The review also delves into the role of advanced therapeutic tools, such as mRNA vaccines and CRISPR-Cas9, in revolutionizing personalized oncology by targeting specific genetic mutations and enhancing immune responses against melanoma. The ongoing synergy between advancing research, targeted interventions, strategic treatment combinations, and cost-effectiveness evaluations offers a promising pathway to elevate patient outcomes in the persistent battle against melanoma significantly.
黑色素瘤是一种侵袭性很强的皮肤癌，给全球健康带来了重大负担，2022年报告了331,647例新病例和58,645例死亡病例。黑色素瘤的发生受多种因素影响，包括阳光照射以及激活MAPK/ERK通路的BRAF突变。BRAF和MEK抑制剂的引入彻底改变了黑色素瘤患者的治疗格局。然而，先天性和获得性治疗耐药性仍然是一个重大挑战。本综述全面概述了黑色素瘤BRAF靶向治疗的现状，重点介绍了美国食品药品监督管理局（FDA）批准的BRAF和MEK抑制剂组合（如维莫非尼、达拉非尼、曲美替尼和考比替尼）的疗效和局限性。该综述还探讨了BRAF抑制剂对内皮细胞的脱靶效应，强调需要更具选择性的疗法，以尽量减少血管并发症和转移潜能。文章还讨论了潜在的可成药靶点，包括ERK5、CD73、ALDH1A1、PLA1A和DMKN，这些靶点在解决诊断障碍和指导个性化治疗决策方面很有前景。关于瑞戈非尼、ERK5信号传导和CD73抑制的最新研究被视为克服耐药性和改善治疗结果的新策略。该综述还深入探讨了先进治疗工具（如mRNA疫苗和CRISPR-Cas9）在通过靶向特定基因突变和增强针对黑色素瘤的免疫反应来彻底改变个性化肿瘤学方面的作用。不断推进的研究、靶向干预、战略治疗组合和成本效益评估之间的协同作用，为在与黑色素瘤的持久战中显著提高患者治疗效果提供了一条充满希望的途径。
