Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors
Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors
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DOI：
10.1158/1535-7163.mct-15-0230
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发表时间：
2015-11-01
影响因子：
5.7
通讯作者：
Jenkins, Emma L.
中科院分区：
文献类型：
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作者：
Davies, Barry R.;Guan, Nin;Jenkins, Emma L.
AKT 1（E17 K）突变在各种实体瘤中发生频率较低，包括乳腺癌和膀胱癌。虽然这种突变已被证明在培养中转化啮齿动物细胞，但发现它比乳腺上皮细胞中的PIK 3CA突变的致癌性更低。此外，AKT抑制剂在具有内源性AKT 1（E17 K）突变的人类肿瘤中的治疗潜力尚不清楚。在MCF 10A乳腺上皮细胞中表达外源性AKT 1（E17 K）增加了AKT及其底物的磷酸化，诱导软琼脂中的集落形成，并在免疫缺陷小鼠的乳腺脂肪垫中形成病变。这些作用分别被别构和催化AKT抑制剂MK-2206和AZD 5363抑制。两种AKT抑制剂都对具有AKT 1 E17 K突变的乳腺癌外植体模型产生了非常显着的生长抑制。此外，在一项I期临床研究中，催化性Akt抑制剂AZD 5363诱导了乳腺癌和卵巢癌患者的部分反应，这些患者的肿瘤含有AKT 1（E17 K）突变。在MGH-U3膀胱癌异种移植物中，含有AKT 1（E17 K）和FGFR 3（Y373 C）突变，AZD 5363单药治疗没有显著减少肿瘤生长，但与FGFR抑制剂AZD 4547联合治疗时观察到肿瘤消退。数据显示，具有AKT 1（E17 K）突变的肿瘤是AKT抑制剂的合理治疗靶点，尽管在同一肿瘤中存在其他蛋白质的激活致癌突变的情况下可能需要与其他靶向药物组合。(C)2015年AACR。
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.