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除外^V600E-突变结直肠癌。达拉非尼联合曲美替尼的组织学不可知论批准标志着二十年来对人类癌症中BRAF突变情况、BRAF 介导的肿瘤发生的生化机制以及选择性 RAF 和 MEK 抑制剂的临床开发研究的顶峰。尽管大多数患有BRAF ^V600E突变肿瘤的患者从基于 BRAF 抑制剂的组合中获得临床益处，但大多数患者都会产生治疗耐药性。在这篇综述中，我们描述了致癌 BRAF 诱导的 MAPK 信号激活的生化基础，以及对 BRAF 抑制剂的内在、适应性和获得性耐药的泛癌和谱系特异性机制。我们还讨论了新型 RAF 抑制剂和药物组合，旨在延迟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。