Anaya Yamile Abuchard, Bracho Ricardo Pequeno, Chauhan Subhash C, Tripathi Manish K, Bandyopadhyay Debasish
School of Integrative Biological and Chemical Sciences, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA.
Department of Health and Human Performance, College of Health Professions, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA.
Int J Mol Sci. 2025 Mar 16;26(6):2676. doi: 10.3390/ijms26062676.
B-RAF is a serine/threonine kinase that plays a crucial role in the MAPK signaling pathway, regulating cell proliferation and survival. Mutations in B-RAF, particularly V600E, are associated with several malignancies, including melanoma, colorectal cancer, and non-small cell lung cancer, making it a key therapeutic target. The development of B-RAF inhibitors, such as Vemurafenib, Dabrafenib, and second-generation inhibitors like Encorafenib, has led to significant advancements in targeted cancer therapy. However, acquired resistance, driven by MAPK pathway reactivation, RAF dimerization, and alternative signaling pathways, remains a major challenge. This review explores the molecular mechanisms of B-RAF inhibitors, their therapeutic efficacy, and resistance mechanisms, emphasizing the importance of combination strategies to enhance treatment outcomes. The current standard of care involves B-RAF and MEK inhibitors, with additional therapies such as EGFR inhibitors and immune checkpoint blockades showing potential in overcoming resistance. Emerging pan-RAF and brain-penetrant inhibitors offer new opportunities for treating refractory cancers, while precision medicine approaches, including genomic profiling and liquid biopsies, are shaping the future of B-RAF-targeted therapy.
B-RAF是一种丝氨酸/苏氨酸激酶，在MAPK信号通路中起关键作用，调节细胞增殖和存活。B-RAF的突变，尤其是V600E突变，与多种恶性肿瘤相关，包括黑色素瘤、结直肠癌和非小细胞肺癌，使其成为一个关键的治疗靶点。B-RAF抑制剂（如维莫非尼、达拉非尼）以及第二代抑制剂（如恩考芬尼）的开发，推动了靶向癌症治疗的重大进展。然而，由MAPK通路重新激活、RAF二聚化和替代信号通路驱动的获得性耐药仍然是一个主要挑战。本综述探讨了B-RAF抑制剂的分子机制、治疗效果和耐药机制，强调了联合策略对提高治疗效果的重要性。当前的标准治疗方案包括B-RAF和MEK抑制剂，其他疗法（如EGFR抑制剂和免疫检查点阻断剂）在克服耐药方面显示出潜力。新兴的泛RAF抑制剂和脑渗透性抑制剂为难治性癌症的治疗提供了新机会，而精准医学方法（包括基因组分析和液体活检）正在塑造B-RAF靶向治疗的未来。
