mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
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DOI：
10.1126/scitranslmed.3005747
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发表时间：
2013-07-31
影响因子：
17.1
通讯作者：
Baselga J
中科院分区：
文献类型：
--
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
PIK3CA基因的激活突变在乳腺癌中频繁发生，针对磷脂酰肌醇3 - 激酶（PI3K）p110α的抑制剂，如BYL719，正在临床试验中进行研究。在对PIK3CA突变的乳腺癌细胞系中对p110α抑制敏感性的相关因素的研究中，我们观察到对BYL719的敏感性（通过细胞增殖评估）与TORC1通路信号传导的完全抑制相关。相反，对BYL719耐药的癌细胞尽管Akt磷酸化受到抑制，但mTORC1信号传导持续活跃。同样，在患者中，pS6（240/4位点）表达（mTORC1信号传导的标志物）与肿瘤对BYL719的反应相关，并且在治疗后疾病进展的患者的肿瘤中发现mTORC1重新激活。在尽管PI3K p110α被阻断但mTORC1信号传导持续存在（即耐药）的PIK3CA突变癌细胞系中，将变构mTORC1抑制剂RAD001与BYL719一起添加到细胞中，在体外和体内都导致了耐药性的逆转。最后，我们发现胰岛素样生长因子1和神经调节蛋白1等生长因子可以激活哺乳动物雷帕霉素靶蛋白（mTOR）并介导对BYL719的耐药性。我们的研究结果表明，同时使用mTORC1抑制剂可能增强针对p110α的药物的临床活性并延缓耐药性的出现。
Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
82.9
作者：
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影响因子：
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作者：
Elkabets, Moshe;Gifford, Ann M.;McAllister, Sandra S.
通讯作者：
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影响因子：
4.8
作者：
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Brugge, JS
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.