PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma.
PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma.
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DOI：
10.1158/0008-5472.can-17-1589
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Enokida H
中科院分区：
文献类型：
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作者：
Yoshino H;Nohata N;Miyamoto K;Yonemori M;Sakaguchi T;Sugita S;Itesako T;Kofuji S;Nakagawa M;Dahiya R;Enokida H
缺氧诱导因子（HIF）的持续激活对于肾细胞癌（RCC）的进展以及对抗血管生成多激酶和mTOR抑制剂的获得性耐药是重要的。最近，开发了HIF 2 α拮抗剂PT 2385和PT 2399，并正在晚期或转移性透明细胞RCC（ccRCC）的I期临床试验中进行评价。然而，预计会对HIF 2 α拮抗剂产生耐药性。在这项研究中，我们确定了由HIF 2 α缺陷激活的信号作为对多激酶抑制剂舒尼替尼耐药的候选介质。我们在体内建立了舒尼替尼耐药肿瘤细胞，并使用CRISPR/Cas9技术创建了这些细胞的HIF 2 α缺陷变体。机制研究表明，丝氨酸生物合成途径的调节剂磷酸甘油酸脱氢酶（PHGDH）在HIF 2 α缺陷型肿瘤细胞中通常与丝氨酸生物合成途径本身一起上调。因此，用PHGDH抑制剂处理通过诱导细胞凋亡在体内和体外减少HIF 2 α缺陷型肿瘤细胞的生长。我们的研究结果将丝氨酸生物合成途径确定为候选治疗靶点的来源，以根除对HIF 2 α拮抗剂耐药的晚期或转移性ccRCC。
Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to anti-angiogenic multi-kinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a Phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the multi-kinase inhibitor sunitinib. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists.