On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.
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DOI：
10.1038/nature19795
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发表时间：
2016-11-03
期刊：
影响因子：
64.8
通讯作者：
Kaelin WG
中科院分区：
文献类型：
--
作者：
Cho H;Du X;Rizzi JP;Liberzon E;Chakraborty AA;Gao W;Carvo I;Signoretti S;Bruick RK;Josey JA;Wallace EM;Kaelin WG
透明细胞肾细胞癌（ccRCC）是最常见的肾癌形式，通常与pVHL肿瘤抑制蛋白失活和随后的HIF2α转录因子积累有关。本研究表明，在原发性和转移性pvhl缺陷ccRCC的临床前模型中，一种直接抑制HIF2α的小分子（PT2399）以靶向方式导致肿瘤消退。然而，pvhl缺陷的ccRCC细胞系对PT2399的敏感性出乎意料地变化，这表明需要预测性的生物标志物。
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2α transcription factor . Here we show that a small molecule (PT2399) that directly inhibits HIF2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion. pVHL-defective ccRCC cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers.