On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

被引：389

作者：

Cho, Hyejin ^{[1
,2
]}

Du, Xinlin ^{[3
]}

Rizzi, James P. ^{[3
]}

Liberzon, Ella ^{[1
,2
]}

Chakraborty, Abhishek A. ^{[1
,2
]}

Gao, Wenhua ^{[1
,2
]}

Carvo, Ingrid ^{[1
,2
,4
]}

Signoretti, Sabina ^{[1
,2
,4
]}

Bruick, Richard K. ^{[5
]}

Josey, John A. ^{[3
]}

Wallace, Eli M. ^{[3
]}

Kaelin, William G., Jr. ^{[1
,2
,6
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA

[3] Peloton Therapeut Inc, Dallas, TX 75235 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75235 USA

[6] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

NATURE | 2016年 / 539卷 / 7627期

关键词：

PAS-B DOMAIN; TRANSCRIPTION FACTOR; CELL; INHIBITION; CARCINOMA; GENE;

D O I：

10.1038/nature19795

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2 alpha transcription factor (also known as EPAS1)(1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2 alpha causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an ontarget fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.

引用

页码：107 / +

页数：16

共 15 条

[1]

HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses [J].