aInstitut National de la Santé et de la Recherche Médicale (INSERM) U981 bDepartment of Medical Oncology, Gustave Roussy Institute (IGR), Villejuif, France.
Curr Opin Oncol. 2013 Nov;25(6):587-93. doi: 10.1097/CCO.0000000000000014.
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.
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.
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.
探讨哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂在乳腺癌及雷帕霉素类药物耐药中的研究进展。临床前和临床研究表明，mTOR 抑制剂可能有助于克服内分泌治疗和曲妥珠单抗的耐药性。尽管人们对此非常感兴趣，但对 mTOR 抑制剂的作用机制和分子反应的认识尚不完全。
临床前研究已经探讨了 mTOR 抑制剂的耐药性，可分为原发性耐药，与不同激酶的扩增或突变有关，或继发性耐药，雷帕霉素类药物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）途径的反馈环。目前正在进行临床试验，以评估雷帕霉素与其他激酶抑制剂（包括 IGF-IR、磷酸肌醇 3-激酶和 MAPK-细胞外信号调节激酶抑制剂）的联合应用。
雷帕霉素耐药的最新研究结果促使人们在临床试验中评估抑制剂的联合应用。本综述总结了目前对雷帕霉素原发性和继发性耐药的认识，以及克服这种耐药性的最新努力。
