Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro.
Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro.
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DOI：
10.1186/bcr3604
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发表时间：
2014-01-23
期刊：
影响因子：
--
通讯作者：
Gee JM
中科院分区：
文献类型：
--
作者：
Jordan NJ;Dutkowski CM;Barrow D;Mottram HJ;Hutcheson IR;Nicholson RI;Guichard SM;Gee JM
PI 3 K/Akt/mTOR信号在内分泌抵抗性乳腺癌（BC）中的上调已经将mTOR确定为与抗激素一起控制抗性的有吸引力的靶标。RAD 001（依维莫司/Afinitor®），一种变构mTOR抑制剂，在这种情况下证明是有价值的;然而，一些患者在治疗期间固有地难治或复发，需要替代策略。在这里，我们评估了新的双重mTORC 1/2 mTOR激酶抑制剂的潜力，例如AZD 8055，通过与ER +内分泌耐药BC细胞中的RAD 001进行比较。在他莫昔芬（TamR）或雌激素剥夺抵抗（MCF 7-X）的体外模型中，单独使用RAD 001或AZD 8055或与抗激素氟维司群联合使用。终点包括生长、细胞增殖（Ki 67）、活力和迁移，通过Western印迹监测PI 3 K/AKT/mTOR信号传导影响。通过免疫细胞化学和RT-PCR研究潜在的ER串扰。RAD 001是MCF 7衍生的TamR和MCF 7-X细胞的弱生长抑制剂（IC 50 ≥1 μM），可快速抑制mTORC 1信号传导，但不抑制mTORC 2/AKT信号传导。相反，AZD 8055可快速抑制mTORC 1和mTORC 2/AKT活性，是TamR（IC 50 18 nM）和MCF 7-X（IC 50 24 nM）以及T47 D衍生的他莫昔芬耐药模型T47 D-tamR（IC 50 19 nM）的高效（P <0.001）生长抑制剂。AZD 8055可显著抑制耐药细胞增殖，增加细胞死亡，减少细胞迁移。此外，用AZD 8055加氟维司群双重处理TamR或MCF 7-X细胞与单独使用任一种药物相比，提供了上级的耐药性生长控制（P <0.05）。AZD 8055与他莫昔芬（P <0.01）或雌激素剥夺（P <0.05）联合处理也能有效抑制内分泌反应性MCF-7细胞。尽管AZD 8055抑制TamR和MCF 7-X中雌激素受体（ER）ser 167磷酸化，但对ER ser 118活性或几种ER调节基因的表达没有影响，表明mTOR激酶抑制剂的影响在很大程度上不依赖于ER。AZD 8055具有ER非依赖性活性的能力通过两种缺乏ER的获得性氟维司群耐药模型的生长抑制（IC 5018和20 nM）得到进一步证明。这是第一份证明双重mTORC 1/2 mTOR激酶抑制剂具有控制获得性内分泌耐药BC的潜力的报告，即使在依维莫司失败的情况下。当与抗激素治疗一起用作内分泌耐药疾病的二线治疗时，这些抑制剂可能证明特别有益，并且在早期内分泌应答阶段也可能与抗激素一起使用以阻碍耐药性的发展。
Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR. RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P <0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P <0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P <0.05). Co-treating with AZD8055 alongside tamoxifen (P <0.01) or oestrogen deprivation (P <0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance.
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影响因子：
15.8
作者：
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影响因子：
45.3
作者：
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影响因子：
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作者：
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影响因子：
45.3
作者：
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通讯作者：
Pujade-Lauraine, Eric
DOI：
10.1186/bcr3493
发表时间：
2013-10-01
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Eccles SA;Aboagye EO;Ali S;Anderson AS;Armes J;Berditchevski F;Blaydes JP;Brennan K;Brown NJ;Bryant HE;Bundred NJ;Burchell JM;Campbell AM;Carroll JS;Clarke RB;Coles CE;Cook GJ;Cox A;Curtin NJ;Dekker LV;Silva Idos S;Duffy SW;Easton DF;Eccles DM;Edwards DR;Edwards J;Evans D;Fenlon DF;Flanagan JM;Foster C;Gallagher WM;Garcia-Closas M;Gee JM;Gescher AJ;Goh V;Groves AM;Harvey AJ;Harvie M;Hennessy BT;Hiscox S;Holen I;Howell SJ;Howell A;Hubbard G;Hulbert-Williams N;Hunter MS;Jasani B;Jones LJ;Key TJ;Kirwan CC;Kong A;Kunkler IH;Langdon SP;Leach MO;Mann DJ;Marshall JF;Martin L;Martin SG;Macdougall JE;Miles DW;Miller WR;Morris JR;Moss SM;Mullan P;Natrajan R;O'Connor JP;O'Connor R;Palmieri C;Pharoah PD;Rakha EA;Reed E;Robinson SP;Sahai E;Saxton JM;Schmid P;Smalley MJ;Speirs V;Stein R;Stingl J;Streuli CH;Tutt AN;Velikova G;Walker RA;Watson CJ;Williams KJ;Young LS;Thompson AM
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