Molecular Pathways and Mechanisms of BRAF in Cancer Therapy.
Molecular Pathways and Mechanisms of BRAF in Cancer Therapy.
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BRAF在癌症治疗中的分子途径和机制。
DOI：
10.1158/1078-0432.ccr-21-2138
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发表时间：
2022-11-01
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随着在多种恶性肿瘤中识别BRAF中的激活突变，大量努力被放置在设计安全和有效的治疗策略以靶向BRAF。这些努力已经导致三种BRAF抑制剂以及五种BRAF抑制剂加额外药剂的组合的开发和监管批准，以管理癌症，例如黑素瘤、非小细胞肺癌、间变性甲状腺癌和结肠直肠癌。到目前为止，每种方案仅对携带BRAFV 600突变的肿瘤患者有效，并且获益的持续时间通常很短。阻碍BRAF突变型恶性肿瘤的最佳管理的进一步限制是非V600 BRAF突变的治疗不太深刻，并且联合治疗可能需要克服耐药机制，但多药方案通常毒性太大。随着对BRAF突变如何通过RAS/丝裂原活化蛋白激酶（MAPK）途径发出信号的更深入理解的出现，正在开发新的RAF抑制剂，其可能更有效，并且正在临床上测试潜在的更安全和更合理的组合疗法。在这篇综述中，我们通过RAS/MAPK通路识别RAF信号传导的机制，介绍了单药和组合RAF靶向努力的现有数据，描述了新兴的组合，总结了临床试验中各种药物的毒性，并推测该领域可能走向何方。
With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/mitogen activated protein kinase (MAPK) pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.