Drug Development Unit, Sarah Cannon Research Institute, 93 Harley Street, London, W1G 6AD, UK.
Guy's and St. Thomas' Hospital, Great Maze Pond, London, SE1 9RT, UK.
Cancer Chemother Pharmacol. 2021 Mar;87(3):437-441. doi: 10.1007/s00280-021-04234-0. Epub 2021 Feb 3.
The management of cancer has been traditionally dependent on the primary tumour type and specific histologic subtypes. Recently, the introduction of molecular profiling tools and its increasing use in clinical practice has facilitated the emergence of novel genomically driven treatment options within the standard of care landscape as well as in the clinical trial setting. One such aberration is mutation in v-Raf murine sarcoma viral oncogene homolog B (BRAF), which results in hyperactivation of RAS-RAF-MEK-ERK signaling in the Mitogen-activated protein kinases (MAPK) pathway. BRAF and Mitogen-activated protein kinase, extracellular signal-regulated kinase kinase (MEK) inhibitors, although being currently approved for melanoma, non-small cell lung cancer (NSCLC) and colon cancer, have reported activity across other various cancers harbouring BRAF aberrations. It has been proposed that combined MEK and BRAF inhibition could overcome the acquired resistance commonly developed among patients receiving BRAF or MEK inhibitors as monotherapy. We report five cases of BRAF V600E (substitution of glutamic acid for valine in codon 600) aberrant refractory metastatic cancers treated with dual BRAF/MEK combination inhibitor therapy leading to an excellent clinical and radiological response and protracted duration of disease control.
癌症的治疗传统上依赖于原发肿瘤类型和特定的组织学亚型。最近，分子谱分析工具的引入及其在临床实践中的广泛应用，促进了新型基于基因组的治疗选择在标准治疗方案以及临床试验环境中的出现。一种这样的异常是 v-Raf 鼠肉瘤病毒致癌基因同源物 B（BRAF）的突变，导致丝裂原激活蛋白激酶（MAPK）通路中 RAS-RAF-MEK-ERK 信号的过度激活。BRAF 和丝裂原激活蛋白激酶、细胞外信号调节激酶激酶（MEK）抑制剂目前虽然被批准用于治疗黑色素瘤、非小细胞肺癌（NSCLC）和结肠癌，但已在其他携带 BRAF 异常的各种癌症中报告了活性。有人提出，联合 MEK 和 BRAF 抑制可能会克服接受 BRAF 或 MEK 抑制剂单药治疗的患者中常见的获得性耐药。我们报告了五例 BRAF V600E（在密码子 600 处谷氨酸取代缬氨酸）异常难治性转移性癌症患者，这些患者接受了双重 BRAF/MEK 联合抑制剂治疗，导致了极好的临床和影像学反应以及疾病控制的持续时间延长。
