Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, UK.
BMC Cancer. 2021 Aug 5;21(1):896. doi: 10.1186/s12885-021-08616-8.
In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed.
We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385.
PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity.
this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.
在透明细胞肾细胞癌中，80%的病例存在 VHL 基因的双等位基因失活，导致 HIF1α 和 HIF2α 的持续激活。由于 HIF2α 是促进肿瘤生长和转移的疾病驱动因素，因此已开发出针对 HIF2α 的药物。然而，耐药性很常见，因此需要新的治疗方法。
我们评估了 HIF2α 拮抗剂 PT2385 在肿瘤发展的几个阶段的作用，并进行了 RNAseq 以鉴定治疗后差异表达的基因。药物筛选用于鉴定对 VHL 突变型 HIF2α 表达细胞具有抗增殖作用并能增加 PT2385 有效性的药物。
PT2385 并未降低细胞增殖或集落形成能力，但与 HIF2α 的基因沉默相反，它降低了体外细胞侵袭。PT2385 治疗后许多 HIF 诱导基因下调，而一些参与细胞迁移或细胞外基质的基因上调。HIF2α 与他汀类药物的耐药性相关，除了 PT2385 之外，增加药物敏感性没有增加。
这项研究表明，抑制靶标与基因敲低之间存在关键差异，这些差异可能是可靶向的。
