Abstract：
OBJECTIVE: BRAF mutations are relatively uncommon in lung cancer. However, the majority of therapies targeting BRAF mutations have been developed exclusively for lung cancer patients with V600E mutations, limiting their effectiveness in treating tumors with the non-V600E BRAF mutations. As a result, there is a need to explore effective therapeutic strategies for patients with lung cancer carrying non-V600 BRAF mutations. Therefore, this study aims to identify a combination treatment approach that effectively targets lung cancer with G469A non-V600 BRAF alteration.
METHODS: The efficacy of drug treatments was assayed using a patient-derived xenograft (PDX) mouse model. Histological analysis was performed using hematoxylin and eosin and immunohistochemical staining. Cell viability and growth were determined using the WST-8 and colony formation assays. Protein levels and apoptosis were analyzed using western blot and flow cytometry, respectively.
RESULTS: We demonstrated that the lung cancer cells harboring the non-V600E G469A mutation were responsive to the combination of SH003 and dabrafenib. By utilizing patient-derived xenograft (PDX) models, we identified that this combined treatment induces apoptosis and exhibits antitumor effects through the reduction of ERK signals. The synergistic effect of the combination treatment on BRAF G469A lung cancer cells was consistent with its effects on PDX models, suggesting that the molecular mechanism of apoptosis involves a decrease in the MEK/ERK signaling pathway.
CONCLUSIONS: The SH003 and dabrafenib combination can be potentially developed as an effective treatment strategy for addressing lung cancer patients with the BRAF G469A mutation.
METHODS: The efficacy of drug treatments was assayed using a patient-derived xenograft (PDX) mouse model. Histological analysis was performed using hematoxylin and eosin and immunohistochemical staining. Cell viability and growth were determined using the WST-8 and colony formation assays. Protein levels and apoptosis were analyzed using western blot and flow cytometry, respectively.
RESULTS: We demonstrated that the lung cancer cells harboring the non-V600E G469A mutation were responsive to the combination of SH003 and dabrafenib. By utilizing patient-derived xenograft (PDX) models, we identified that this combined treatment induces apoptosis and exhibits antitumor effects through the reduction of ERK signals. The synergistic effect of the combination treatment on BRAF G469A lung cancer cells was consistent with its effects on PDX models, suggesting that the molecular mechanism of apoptosis involves a decrease in the MEK/ERK signaling pathway.
CONCLUSIONS: The SH003 and dabrafenib combination can be potentially developed as an effective treatment strategy for addressing lung cancer patients with the BRAF G469A mutation.
摘要：
目的：BRAF突变在肺癌中相对少见。然而,大多数针对BRAF突变的疗法都是专门针对V600E突变的肺癌患者开发的，限制了它们治疗非V600EBRAF突变肿瘤的有效性。因此,对于携带非V600BRAF突变的肺癌患者,有必要探索有效的治疗策略.因此,本研究旨在确定一种有效靶向G469A非V600BRAF改变的肺癌的联合治疗方法.
方法:使用患者来源的异种移植物(PDX)小鼠模型测定药物治疗的功效。使用苏木精和曙红和免疫组织化学染色进行组织学分析。使用WST-8和集落形成测定法测定细胞活力和生长。蛋白质水平和细胞凋亡使用蛋白质印迹和流式细胞术分析，分别。
结果：我们证明了携带非V600EG469A突变的肺癌细胞对SH003和dabrafenib的组合有反应。通过利用患者来源的异种移植物(PDX)模型，我们发现这种联合治疗诱导细胞凋亡,并通过降低ERK信号表现出抗肿瘤作用.联合治疗对BRAFG469A肺癌细胞的协同作用与其对PDX模型的作用一致。提示细胞凋亡的分子机制涉及MEK/ERK信号通路的减少。
结论：SH003和dabrafenib联合用药有可能成为解决BRAFG469A突变肺癌患者的有效治疗策略。
方法:使用患者来源的异种移植物(PDX)小鼠模型测定药物治疗的功效。使用苏木精和曙红和免疫组织化学染色进行组织学分析。使用WST-8和集落形成测定法测定细胞活力和生长。蛋白质水平和细胞凋亡使用蛋白质印迹和流式细胞术分析，分别。
结果：我们证明了携带非V600EG469A突变的肺癌细胞对SH003和dabrafenib的组合有反应。通过利用患者来源的异种移植物(PDX)模型，我们发现这种联合治疗诱导细胞凋亡,并通过降低ERK信号表现出抗肿瘤作用.联合治疗对BRAFG469A肺癌细胞的协同作用与其对PDX模型的作用一致。提示细胞凋亡的分子机制涉及MEK/ERK信号通路的减少。
结论：SH003和dabrafenib联合用药有可能成为解决BRAFG469A突变肺癌患者的有效治疗策略。
