Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China.
Target Oncol. 2024 Sep;19(5):691-703. doi: 10.1007/s11523-024-01080-x. Epub 2024 Jul 11.
The mitogen-activated protein kinase (MAPK) pathway is a key driver in many histiocytic disorders, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). This has led to successful and promising treatment with targeted therapies, including BRAF inhibitors and MEK inhibitors. Additional novel inhibitors have also demonstrated encouraging results. Nevertheless, there are several problems concerning targeted therapy that need to be addressed. These include, among others, incomplete responsiveness and the emergence of resistance to BRAF inhibition as observed in other BRAF-mutant malignancies. Drug resistance and relapse after treatment interruption remain problems with current targeted therapies. Targeted therapy does not seem to eradicate the mutated clone, leading to inevitable relapes, which is a huge challenge for the future. More fundamental research and clinical trials are needed to address these issues and to develop improved targeted therapies that can overcome resistance and achieve long-lasting remissions.
丝裂原活化蛋白激酶（MAPK）通路是许多组织细胞疾病的关键驱动因素，包括朗格汉斯细胞组织细胞增生症（LCH）和 Erdheim-Chester 病（ECD）。这导致了靶向治疗的成功和有前景的结果，包括 BRAF 抑制剂和 MEK 抑制剂。其他新型抑制剂也显示出令人鼓舞的结果。然而，靶向治疗仍存在一些需要解决的问题。其中包括不完全应答以及 BRAF 抑制耐药的出现，如其他 BRAF 突变恶性肿瘤中观察到的那样。治疗中断后耐药和复发仍然是当前靶向治疗的问题。靶向治疗似乎并不能根除突变克隆，导致不可避免的复发，这是未来的巨大挑战。需要更多的基础研究和临床试验来解决这些问题，并开发能够克服耐药性并实现持久缓解的改良靶向治疗。
