Targeting renal cell carcinoma with a HIF-2 antagonist.
Targeting renal cell carcinoma with a HIF-2 antagonist.
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DOI：
10.1038/nature19796
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发表时间：
2016-11-03
期刊：
影响因子：
64.8
通讯作者：
Brugarolas J
中科院分区：
文献类型：
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作者：
Chen W;Hill H;Christie A;Kim MS;Holloman E;Pavia-Jimenez A;Homayoun F;Ma Y;Patel N;Yell P;Hao G;Yousuf Q;Joyce A;Pedrosa I;Geiger H;Zhang H;Chang J;Gardner KH;Bruick RK;Reeves C;Hwang TH;Courtney K;Frenkel E;Sun X;Zojwalla N;Wong T;Rizzi JP;Wallace EM;Josey JA;Xie Y;Xie XJ;Kapur P;McKay RM;Brugarolas J
透明细胞肾细胞癌（ccRCC）的特征是VHL失活。因为没有其他基因突变频繁，VHL突变是截断，VHL失活被认为是主导事件。VHL损失激活HIF-2，并且组成型HIF-2恢复VHL重建的ccRCC细胞中的肿瘤发生。HIF-2参与血管生成和其他多种过程，但血管生成是舒尼替尼等药物的主要靶点。HIF-2是一种转录因子，一直被认为是不可治疗的。基于结构的设计方法确定了一种选择性HIF-2拮抗剂（PT 2399），我们使用肿瘤移植物（TG）/PDX平台进行评估。PT 2399在人ccRCC中解离HIF-2（一种专性异源二聚体[HIF-2α/HIF-1β]），在56%（10/18）的细胞系中抑制肿瘤发生。PT 2399比舒尼替尼具有更大的活性，在舒尼替尼进展的肿瘤中具有活性，并且耐受性更好。出乎意料的是，一些VHL突变型ccRCC具有抗性。尽管肿瘤中的HIF-2解离和通过抑制循环促红细胞生成素（HIF-2靶标和可能的药效学标记物）确定的小鼠中的HIF-2抑制的证据，但仍发生抗性。我们在敏感肿瘤中鉴定了一个HIF-2依赖性基因签名。说明药物特异性，基因表达在耐药肿瘤中基本上不受PT 2399的影响。敏感性肿瘤表现出独特的基因表达特征，并且通常具有较高的HIF-2α水平。延长PT 2399治疗导致耐药性。我们在HIF-2α和HIF-1β中分别发现了一个结合位点和第二个位点的抑制突变。尽管用PT 2399处理，两种突变都保留了HIF-2二聚体。最后，一名经过广泛预治疗的敏感性TG患者使用相似的PT 2385控制了疾病>11个月。我们验证了HIF-2作为ccRCC中的靶点，表明一些ccRCC出乎意料地独立于HIF-2，并为生物标志物驱动的临床试验奠定了基础。
Clear cell Renal Cell Carcinoma (ccRCC) is characterized by VHL inactivation. Because no other gene is mutated as frequently, and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates HIF-2, and constitutive HIF-2 restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 is implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs like sunitinib. HIF-2, a transcription factor, has been regarded as undruggable. A structure-based design approach identified a selective HIF-2 antagonist (PT2399) that we evaluate using a tumorgraft (TG)/PDX platform. PT2399 dissociated HIF-2 (an obligatory heterodimer [HIF-2α/HIF-1β]) in human ccRCC suppressing tumorigenesis in 56% (10/18) lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumors, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant. Resistance occurred despite HIF-2 dissociation in tumors and evidence of Hif-2 inhibition in the mouse as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumors. Illustrating drug specificity, gene expression was largely unaffected by PT2399 in resistant tumors. Sensitive tumors exhibited a distinguishing gene expression signature, and generally higher HIF-2α levels. Prolonged PT2399 treatment led to resistance. We identified a binding site and second site suppressor mutation in HIF-2α and HIF-1β respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient with a sensitive TG had disease control for >11 months with the close analogue PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCC are, unexpectedly, HIF-2 independent, and set the stage for biomarker-driven clinical trials.