Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Department of Biomedical Engineering, Oregon Health and Science University Center for Spatial Systems Biomedicine, Portland, OR, USA.
Cell Rep Med. 2021 May 7;2(5):100267. doi: 10.1016/j.xcrm.2021.100267. eCollection 2021 May 18.
The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression . Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.
晚期非透明细胞肾细胞癌（NCCRCC）缺乏有效治疗方案，这是一个亟待解决的临床难题。我们采用高通量药物筛选方法，对多种人肾癌细胞进行检测，发现血管内皮生长因子受体-间质表皮转化因子（VEGFR-MET）抑制剂卡博替尼（cabozantinib）与Src 抑制剂达沙替尼（dasatinib）联合应用，可协同作用于细胞，显著降低细胞活力。重要的是，该联合用药具有良好的耐受性，并能引起肿瘤消退。转录组和磷酸蛋白质组学分析表明，该联合用药可集中下调丝裂原活化蛋白激酶-细胞外信号调节激酶（MAPK-ERK）信号通路，这一结果不能仅通过单一药物分析预测。相应地，添加 MEK 抑制剂与达沙替尼或卡博替尼协同作用，可提高其疗效。本研究采用已批准的、具有临床相关性的药物，为设计可快速转化为临床应用的 NCCRCC 有效联合治疗方案提供了依据。
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