Department of Surgery/Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
PLoS One. 2013;8(1):e54918. doi: 10.1371/journal.pone.0054918. Epub 2013 Jan 22.
Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC). Currently approved agents inhibit mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells) cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794.
雷帕霉素类似物，替西罗莫司和依维莫司，被批准用于治疗晚期肾细胞癌（RCC）。目前批准的药物抑制雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）。然而，mTOR 激酶存在于两个不同的多蛋白复合物中，mTORC1 和 mTORC2，并且这两个复合物可能都是细胞代谢、生长和增殖的关键调节因子。此外，有人提出，在使用替西罗莫司或依维莫司治疗期间，由于 mTORC2 信号的代偿激活而产生耐药性。我们评估了 Ku0063794，它是一种抑制两种 mTOR 复合物的小分子。Ku0063794 在肾细胞癌的临床前模型中与替西罗莫司进行了比较。Ku0063794 有效抑制了 mTORC1 和 mTORC2 下游信号蛋白的磷酸化，包括 p70 S6K、4E-BP1 和 Akt。与替西罗莫司相比，Ku0063794 在体外通过诱导细胞周期停滞和自噬而不是凋亡，更有效地降低了 RCC 细胞系 Caki-1 和 786-O 的活力和生长。然而，在异种移植模型中，Ku0063794 或替西罗莫司对肿瘤生长的抑制没有差异。一个潜在的解释是替西罗莫司对肿瘤微环境还有其他作用。与这种可能性一致的是，替西罗莫司而非 Ku0063794 降低了体内肿瘤血管生成，并降低了在药理学相关浓度下的人脐静脉内皮细胞（HUVEC）细胞的活力。此外，在 Caki-1 和 786-O 细胞中，与用 Ku0063794 处理的细胞相比，用替西罗莫司处理的细胞中 VEGF 和 PDGF 的表达水平较低。
