In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAF^V600E-mutant solid tumours, except for BRAF^V600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAF^V600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.

2022 年 6 月，FDA 加速批准 BRAF 抑制剂达拉非尼与 MEK 抑制剂曲美替尼联合用于治疗患有不可切除或转移性 BRAF^V600E 突变实体瘤的成人和儿童患者（≥6 岁），BRAF^V600E 突变结直肠癌除外。达拉非尼联合曲美替尼与组织学无关的批准标志着对人类癌症中 BRAF 突变前景、BRAF 介导的肿瘤发生的生化机制以及选择性 RAF 和 MEK 抑制剂的临床开发二十年研究达到顶峰。尽管大多数 BRAF^V600E 突变肿瘤患者从基于 BRAF 抑制剂的组合中获得临床益处，但大多数人对治疗产生耐药性。在本综述中，我们描述了致癌 BRAF 诱导的 MAPK 信号传导激活和泛癌的生化基础，以及对 BRAF 抑制剂的内在、适应性和获得性耐药的谱系特异性机制。我们还讨论了旨在延缓治疗耐药性的出现和/或扩大受益于分子靶向治疗的 BRAF 突变癌症患者群体的新型 RAF 抑制剂和药物组合。