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首页> 外文期刊>Molecular cancer therapeutics >Tumors with AKT1(E17K) Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors
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Tumors with AKT1(E17K) Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors

机译：具有AKT1（E17K）突变的肿瘤是具有AKT抑制剂的单药剂或组合治疗的合理靶标

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AKT1(E17K) mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1(E17K) mutation is not known. Expression of exogenous copies of AKT1(E17K) in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1(E17K) mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1(E17K) and FGFR3(Y373C) mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1(E17K) mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. (C) 2015 AACR.
机译：AKT1（E17K）突变在各种实体瘤中以低频发生，包括乳腺和膀胱的血管。虽然已经显示出这种突变来转化培养物中的啮齿动物细胞，但发现比乳腺上皮细胞中的PIK3CA突变更少致癌。此外，不知道具有内源AKT1（E17K）突变的人肿瘤中AKT抑制剂的治疗潜力是不知道的。 AKT1（E17K）外源拷贝在MCF10A乳腺上皮细胞的表达增加AKT及其基材的磷酸化，软琼脂中的菌落形成，以及在免疫缺陷小鼠乳腺脂肪垫中的形成。这些效果分别被变形和催化AKT抑制剂MK-2206和AZD5363抑制。两个AKT抑制剂均导致乳腺癌癌症模型的显着增长抑制，AKT1E17K突变。此外，在I期临床研究中，催化AKT抑制剂AZD5363患者患有乳腺癌和卵巢癌患者的部分反应，肿瘤患有Akt1（E17K）突变。在含有Akt1（E17K）和FGFR3（Y373C）突变的MGH-U3膀胱癌异种移植物中，AZD5363单疗法没有显着降低肿瘤生长，但与FGFR抑制剂AZD4547组合观察肿瘤消退。数据显示，具有AKT1（E17K）突变的肿瘤是AKT抑制剂的合理治疗靶标，尽管可能需要与其他靶向剂的组合，其中其他蛋白质的激活致癌突变存在于同一肿瘤中。 （c）2015年AACR。

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