New strategies to overcome resistance to mammalian target of rapamycin inhibitors in breast cancer
New strategies to overcome resistance to mammalian target of rapamycin inhibitors in breast cancer
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DOI：
10.1097/cco.0000000000000014
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发表时间：
2013-11
影响因子：
3.4
通讯作者：
C. Vicier;M. Dieci;F. André
中科院分区：
文献类型：
--
作者：
C. Vicier;M. Dieci;F. André
综述了雷帕霉素（rapamycin, mTOR）抑制剂在哺乳动物乳腺癌中的靶点及对雷帕霉素的耐药研究进展。临床前和临床研究表明，mTOR抑制剂可能有助于克服对内分泌治疗和曲妥珠单抗的耐药性。尽管有很多兴趣，但对mTOR抑制剂的机制和分子反应的了解尚不完整。对mTOR抑制剂的耐药已经在临床前研究中进行了探索，可定义为原发性耐药，与不同激酶的扩增或突变相关，或继发性耐药，其中rapalog激活涉及胰岛素样生长因子I受体（IGF-IR）、血小板衍生生长因子受体和丝裂原活化蛋白激酶（MAPK）途径的反馈回路。目前的临床试验正在测试雷帕霉素与其他激酶抑制剂的组合，包括IGF-IR、磷酸肌肽3-激酶和mapk -细胞外信号调节激酶抑制剂。最近对rapalog耐药的研究结果刺激了对临床试验中抑制剂组合的评估。本文综述了目前对原发和继发耐药的认识，以及目前克服这种耐药的努力。
Purpose of review To review the studies addressing mammalian target of rapamycin (mTOR) inhibitors in breast cancer and resistance to rapalogs. Preclinical and clinical studies have suggested mTOR inhibitors may help overcome the resistance to endocrine therapy and trastuzumab. Despite much interest, knowledge of the mechanism and molecular response to mTOR inhibitors is incomplete. Recent findings Resistance to mTOR inhibitors has been explored in preclinical studies and can be defined as primary, associated with amplifications or mutations of different kinases, or secondary, in which rapalog activates the feedback loops involving the insulin-like growth factor I receptor (IGF-IR), platelet-derived growth factor receptor and mitogen-activated protein kinase (MAPK) pathway. Current clinical trials are testing the combinations of rapamycin with other kinase inhibitors including IGF-IR, phosphoinositide 3-kinase and MAPK-extracellular signal-regulated kinase inhibitors. Summary Recent findings on the resistance to rapalogs have stimulated the assessment of combinations of inhibitors in clinical trials. This review summarizes the current knowledge of primary and secondary rapalog resistance, and the current efforts to overcome this resistance.