The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.
The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.
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DOI：
10.1007/s10549-014-3201-6
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发表时间：
2015-01
影响因子：
3.8
通讯作者：
Miller TW
中科院分区：
文献类型：
--
作者：
Bean JR;Hosford SR;Symonds LK;Owens P;Dillon LM;Yang W;Shee K;Schwartz GN;Marotti JD;Muller KE;Rosenkranz KM;Barth RJ;Chen VS;Agarwal VR;Miller TW
磷脂酰肌醇3-激酶(PI3K)/AKT/mTOR通路的激活与乳腺癌的抗雌激素耐药有关。我们在一组雌激素敏感和耐药的ER+乳腺癌模型中测试了新型PI3K/mTOR双重抑制剂P7170的治疗潜力。雌激素受体阳性(ER+)乳腺癌细胞处理+/−P7170。对2例原发ER+/HER2−肿瘤的新鲜核心进行了+/−P7170的体外治疗。携带乳腺癌异种移植瘤的小鼠被随机分为赋形剂、富维司琼、P7170或其组合治疗，并测量肿瘤体积。分析组织和细胞的途径活性、细胞活力和细胞凋亡的标志物。在细胞株中，P7170的IC50值在0.9-7 nM范围内，并诱导细胞凋亡。P7170能有效地抑制mTOR活性(≤25nM)，并在较高浓度下(≥200nM)抑制PI3K。P7170完全抑制MCF-7肿瘤生长，显著抑制耐药肿瘤T47D的生长，抑制肿瘤细胞增殖，但不诱导细胞凋亡。P7170在体外抑制ER+/HER2−人乳腺癌细胞和肿瘤细胞的PI3K和mTOR，而体内实验数据表明P7170的抗肿瘤作用的主要机制是抑制mTOR和细胞增殖。P7170是一种值得进一步研究的治疗ER阳性乳腺癌的新药物。
Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and -resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated +/− P7170. Fresh cores from primary ER+/HER2− tumors from two patients were treated +/− P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤25 nM), and inhibited PI3K at higher concentrations (≥200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2− human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.
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影响因子：
3.9
作者：
Destefano MA;Jacinto E
通讯作者：
Jacinto E
影响因子：
11.2
作者：
Miller TW;Pérez-Torres M;Narasanna A;Guix M;Stål O;Pérez-Tenorio G;Gonzalez-Angulo AM;Hennessy BT;Mills GB;Kennedy JP;Lindsley CW;Arteaga CL
通讯作者：
Arteaga CL
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.
影响因子：
8.8
作者：
Janku F;Hong DS;Fu S;Piha-Paul SA;Naing A;Falchook GS;Tsimberidou AM;Stepanek VM;Moulder SL;Lee JJ;Luthra R;Zinner RG;Broaddus RR;Wheler JJ;Kurzrock R
通讯作者：
Kurzrock R