Department of Nephrology, The Second People's Hospital of Yibin, Yibin, Sichuan, 644000, PR China.
Department of Urology, Tangdu Hospital, Air Force Medical University, Xi'an, Shanxi, 710038, PR China.
Future Oncol. 2021 Aug;17(23):3051-3060. doi: 10.2217/fon-2021-0256. Epub 2021 Apr 28.
The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs. Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway. Cobimetinib was active against RCC cells, with IC at 0.006-0.8μM, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition. Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.
晚期肾细胞癌（RCC）的预后较差，需要新的治疗方法。考比替尼是一种 MEK 抑制剂，已被批准用于治疗黑色素瘤。本研究探讨了考比替尼单独使用和与抗 RCC 药物联合使用的疗效。在 RCC 细胞系（CaKi-2、786-O、A-704、ACHN 和 A489）和异种移植模型中进行了增殖和凋亡测定，并分析了合并指数。通过免疫印迹分析研究了 MAPK 通路。考比替尼对 RCC 细胞具有活性，IC 在 0.006-0.8μM 之间，与标准治疗方案具有协同作用。考比替尼在无毒剂量下可预防肿瘤形成，抑制肿瘤生长，并通过抑制 Raf/MEK/ERK 增强 5-氟尿嘧啶、索拉非尼和舒尼替尼的疗效，从而抑制 MAPK 通路。我们的研究结果表明，考比替尼具有强大的抗 RCC 活性，并且与 RCC 标准治疗药物具有协同作用，并证实了考比替尼作用的潜在机制。
