Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma.
Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma.
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DOI：
10.18632/oncotarget.2372
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发表时间：
2014-09-30
期刊：
影响因子：
--
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Moore NF;Azarova AM;Bhatnagar N;Ross KN;Drake LE;Frumm S;Liu QS;Christie AL;Sanda T;Chesler L;Kung AL;Gray NS;Stegmaier K;George RE
ALK酪氨酸激酶受体基因突变是神经母细胞瘤的重要治疗靶点，但其临床转化一直具有挑战性。ALKF1174L突变仅在高剂量时对ALK抑制剂克唑替尼敏感，并介导ALK易位癌症对克唑替尼的获得性耐药。我们已经证明，在携带ALKF1174L/ mycn阳性神经母细胞瘤的转基因小鼠中，克唑替尼和一种下游信号抑制剂联合使用可诱导良好的应答。在这里，我们研究了这种效应的分子基础，并评估了类似的策略是否对缺乏MYCN过表达的alk突变肿瘤有效。我们发现，在alk突变、mycn扩增的神经母细胞瘤细胞中，单独克唑替尼不会影响mTORC1活性，正如持续的RPS6磷酸化所表明的那样。与单药治疗相比，在ALKF1174L/ mycn阳性模型中，克唑替尼和atp竞争性mTOR抑制剂联合治疗可消除RPS6磷酸化，从而降低肿瘤生长并延长生存期。相比之下，这种组合在诱导mTORC1下调的同时，在表达野生型MYCN的alk突变细胞中引起PI3K活性的相互上调。在这里，一种同时对抗mTOR和PI3K的抑制剂在与克唑替尼联合使用时更有效地促进细胞毒性。我们的发现应该能够更精确地为alk突变肿瘤患者选择分子靶向药物。
Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALKF1174L mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALKF1174L/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALKF1174L/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors.
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影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
50.3
作者：
Armstrong, SA;Kung, AL;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
DOI：
10.1073/pnas.1108237108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Ilic, Nina;Utermark, Tamara;Roberts, Thomas M.
通讯作者：
Roberts, Thomas M.
影响因子：
28.2
作者：
Rodrik-Outmezguine VS;Chandarlapaty S;Pagano NC;Poulikakos PI;Scaltriti M;Moskatel E;Baselga J;Guichard S;Rosen N
通讯作者：
Rosen N
影响因子：
14.5
作者：
Azarova AM;Gautam G;George RE
通讯作者：
George RE