文章：

靶向脑肿瘤中的MAPK通路：机制与治疗机遇

Targeting the MAPK Pathway in Brain Tumors: Mechanisms and Therapeutic Opportunities

原文发布日期：2 January 2026

DOI: 10.3390/cancers18010156

类型: Article

开放获取: 是

英文摘要：

Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such asBRAF V600Eand oncogenic fusions likeBRAF–KIAA1549are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors.

摘要翻译： 

中枢神经系统肿瘤是一组生物学复杂、发病率高且对现有疗法反应有限的恶性肿瘤，在临床上仍面临巨大挑战。越来越多的基因组学证据表明，丝裂原活化蛋白激酶信号通路的失调是许多儿童及成人中枢神经系统肿瘤中普遍存在的共同特征。影响上游受体酪氨酸激酶、RAS GTP酶、RAF激酶及其他相关调节因子的改变导致MAPK信号通路过度激活，从而塑造肿瘤行为、治疗反应及耐药性。从BRAF V600E热点突变到BRAF–KIAA1549致癌融合等异常改变在胶质瘤和胶质神经元肿瘤中尤为富集，凸显MAPK信号通路作为关键致癌驱动因素的作用。随着RAF、MEK和ERK选择性抑制剂等分子靶向化合物的日益丰富，针对特定分子亚型的治疗方法已开始发生转变。然而，MAPK靶向治疗的临床获益常受限于血脑屏障穿透性不足、肿瘤内异质性、平行通路再激活以及免疫抑制性肿瘤微环境等因素。本文综述了当前关于中枢神经系统肿瘤中MAPK通路改变的研究进展，系统评估了MAPK抑制剂的治疗格局，重点探讨已获批药物、新兴化合物、联合治疗策略及新型药物递送技术。同时分析了影响治疗效果的内在机制，并展望未来将MAPK靶向治疗整合进脑肿瘤精准化管理的发展方向。

原文链接：

Targeting the MAPK Pathway in Brain Tumors: Mechanisms and Therapeutic Opportunities