Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
Leuven Cancer Institute (LKI), B-3000 Leuven, Belgium.
Int J Mol Sci. 2018 Aug 13;19(8):2380. doi: 10.3390/ijms19082380.
Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.
Ⅱ型子宫内膜癌（EC）由于其侵袭性、晚期检测和对标准治疗的高耐受性，是导致大多数与子宫内膜癌相关的死亡的原因。然而，目前还没有针对Ⅱ型 EC 的靶向治疗方法，它们仍然与临床上惰性和易于治疗的Ⅰ型 EC 一样进行治疗。因此，Ⅱ型 EC 需要新的治疗选择。最近，对子宫内膜癌的分子分析显示，磷酸肌醇-4,5-二磷酸 3-激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）途径中的磷酸化依赖性致癌信号在Ⅱ型 EC 中最常发生改变。因此，临床试验测试了针对这些途径的药理激酶抑制剂，但大多结果令人失望。在这篇综述中，我们强调了Ⅱ型 EC 中最常见的遗传改变。此外，我们还解释了为什么大多数使用靶向激酶抑制剂的 EC 临床试验结果不尽如人意，以及未来临床试验设计中应做出哪些改变。此外，我们认为，除了激酶之外，磷酸酶在临床试验中也不应再被忽视，特别是在Ⅱ型 EC 中，肿瘤抑制性磷酸酶蛋白磷酸酶 2A（PP2A）经常发生突变。最后，我们讨论了针对（重新）激活 PP2A 的治疗潜力，可能与药理激酶抑制剂联合使用。
