Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL-/- ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors.

中文翻译：

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物种间CDK4 / 6抑制与VHL损失之间不依赖HIF的合成致死率。

VHL抑癌基因的失活是肾癌最常见的形式-透明细胞肾细胞癌（ccRCC）中的标志性启动事件，并导致缺氧诱导因子2α（HIF-2α）的积累。HIF-2α抑制剂在某些ccRCC病例中有效，但是从头和获得性耐药均已在实验室和临床中观察到。在这里，我们确定了两种物种（人和果蝇）中以及培养和异种移植物中不同的人ccRCC细胞系中细胞周期蛋白依赖性激酶4和6（CDK4 / 6）的活性降低和VHL失活之间的合成致死性。尽管HIF-2α转录诱导CDK4 / 6伴侣细胞周期蛋白D1，但对于VHL-/-ccRCC细胞增加的CDK4 / 6需求，HIF-2α并不是必需的。因此，CDK4 / 6抑制的抗增殖作用与HIF-2α依赖性VHL-/-ccRCC细胞中的HIF-2α抑制作用协同，而不与HIF-2α依赖性细胞中的HIF-2α抑制作用拮抗。这些发现支持单独或与HIF-2α抑制剂联合测试CDK4 / 6抑制剂作为ccRCC的治疗方法。