The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer.
The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer.
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DOI：
10.6004/jnccn.2013.0086
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发表时间：
2013-06-01
期刊：
影响因子：
--
通讯作者：
Wolff AC
中科院分区：
文献类型：
--
作者：
Lauring J;Park BH;Wolff AC
磷酸肌醇-3-激酶 (PI3-激酶)-Akt-mTOR 通路是一条中央信号转导通路，调节正常和癌症生理学的许多关键方面，包括细胞增殖、凋亡、细胞形态和迁移、蛋白质合成和代谢整合。在乳腺癌中，激活该通路的体细胞突变发生在超过 50% 的肿瘤中，这凸显了靶向该通路治疗的潜在广泛影响。大量临床前数据证明了通路抑制对肿瘤生长的功效，并且证据还表明该通路的激活发生在激素治疗获得性耐药模型中。这项临床前工作引发了对变构 mTOR 抑制剂依维莫司和替西罗莫司治疗转移性激素受体阳性乳腺癌的研究。最近的 BOLERO-2 试验比较了依维莫司加依西美坦与安慰剂加依西美坦治疗对非甾体芳香酶抑制剂耐药的女性，结果显示无进展生存期延长了 6 个月，并导致美国 FDA 批准依维莫司用于该适应症。这项具有里程碑意义的试验首次证明了使用针对乳腺癌这一途径的药物具有显着的临床益处。关于依维莫司和其他通路靶向药物在乳腺癌治疗临床开发中的作用仍然存在许多问题。本文回顾了 PI3-kinase-Akt-mTOR 通路在乳腺癌生物学中的作用以及迄今为止可用的临床试验证据。
The phosphoinositide-3-kinase (PI3-kinase)-Akt-mTOR pathway is a central signal transduction pathway that regulates many critical aspects of normal and cancer physiology, including cell proliferation, apoptosis, cell morphology and migration, protein synthesis, and integration of metabolism. In breast cancer, somatic mutations that activate the pathway occur in more than 50% of tumors, underscoring the potentially broad impact of targeting the pathway for therapy. A vast body of preclinical data demonstrates the efficacy of pathway inhibition on tumor growth, and evidence also shows that activation of the pathway occurs in models of acquired resistance to hormonal therapy. This preclinical work led to the investigation of allosteric mTOR inhibitors, everolimus and temsirolimus, in metastatic hormone receptor–positive breast cancer. The recent BOLERO-2 trial comparing everolimus plus exemestane versus placebo plus exemestane in women with resistance to nonsteroidal aromatase inhibitors demonstrated a 6-month improvement in progression-free survival and led to FDA approval of everolimus for this indication in the United States. This landmark trial is the first demonstration of significant clinical benefit using drugs targeting this pathway in breast cancer. Many questions remain about the role of everolimus and other pathway-targeting drugs in clinical development in breast cancer treatment. This article reviews the role of the PI3-kinase-Akt-mTOR pathway in breast cancer biology and the clinical trial evidence available to date.
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