联合应用BRAF和MEK抑制剂是一种活跃的治疗方案，适用于具有BRAF V600E突变的肿瘤患者；然而，这种疗法的临床疗效受到抗药性的限制。预临床研究表明，加入热休克蛋白90（HSP90）抑制剂可提高BRAF抑制剂治疗BRAF抑制剂敏感和BRAF抑制剂耐药突变细胞系的疗效。癌症治疗评估计划研究9557（ClinicalTrials.gov标识符NCT02097225）是一项Ⅰ期研究，旨在评估小分子HSP90抑制剂AT13387与dabrafenib和trametinib联合治疗BRAF V600E / K突变实体肿瘤的安全性和疗效。相关分析评估了HSP90客户蛋白和伴侣蛋白的表达。22名转移性BRAF V600E突变实体肿瘤患者使用3 + 3设计在四个剂量水平上入组，21名患者可用于疗效评估。最常见的肿瘤类型是结肠直肠癌（N = 12）。剂量限制性毒性在第3剂量水平的一名患者和第4剂量水平的一名患者中发生，具体为骨髓抑制和疲劳。最大耐受剂量是口服dabafenib 150 mg两次/天，口服trametinib 2 mg一次/天，静脉注射AT13387 260 mg/m2，第1、8、15天。最佳反应为2名患者局部缓解，8名患者稳定病情，总体反应率为9.5%（90%确切置信区间[CI]，2％-27％），疾病控制率为47.6％（90％CI，29％-67％），中位总生存期为5.1个月（90％CI，3.4-7.6个月）。没有与响应或耐药性相关的一致性蛋白质组变化，尽管响应者具有BRAF表达减少，其中一名患者的结直肠癌使用HSP90抑制剂发现表皮生长因子受体下调。HSP90抑制联合BRAF/ MEK抑制是安全的，并在强烈预处理的人群中产生了适度的疾病控制证据。其他转化工作可能会确定对这种方法最敏感的肿瘤类型和耐药机制。 © 2023 American Cancer Society.

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer.HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.© 2023 American Cancer Society.