Johnston S R D
Department of Medicine-Breast Unit, Royal Marsden Hospital, London, United Kingdom.
Int J Gynecol Cancer. 2006;16 Suppl 2:543-8. doi: 10.1111/j.1525-1438.2006.00692.x.
In breast cancer, there is an increasing recognition of the pivotal role played by the epidermal growth factor receptor (EGFR) and HER2 together with the various downstream signal transduction pathways, in particular the Ras/Raf/Mek/erk1/2 pathway that regulates cell proliferation together with the phosphatidylinositol-3-OH kinase (PI3K)/Akt/mTOR pathway that is implicated in cell survival. While monoclonal antibodies and small molecule tyrosine kinase inhibitors targeted against EGFR/HER2 are now being used for breast cancer therapy, there is considerable interest in also targeting the critical downstream pathways that cells may remain dependent upon. Activation of these downstream pathways in breast cancer may be associated with resistance to either conventional endocrine or cytotoxic therapies or, indeed, lack of response to EGFR/HER2-targeted approaches. Farnesyltransferase inhibitors (FTIs) were initially developed to target Ras activation, although their mechanism of action may be more nonspecific. Trials in breast cancer have been completed with FTIs alone or in combination with endocrine or cytotoxic therapy. Activation of the PI3K/Akt pathway has also been associated with resistance to either tamoxifen or estrogen deprivation, and preclinical studies have shown that the mTOR antagonists can restore endocrine sensitivity in breast cancer cells. Randomized phase II/III trials of aromatase inhibitors combined with mTOR antagonists are in progress and have been powered to detect whether combined therapy can significantly prolong time to disease progression compared to endocrine therapy alone. Finally, preclinical experiments are now investigating whether downstream agents should be combined with upstream EGFR/HER2 therapies to produce maximal blockade of vertical signal transduction pathways. Subsequent trials will be needed to see whether combinations of novel STIs are well tolerated and how they may further enhance clinical benefit in breast cancer.
在乳腺癌中，表皮生长因子受体（EGFR）和HER2以及各种下游信号转导通路所起的关键作用日益受到认可，特别是调节细胞增殖的Ras/Raf/Mek/erk1/2通路以及与细胞存活相关的磷脂酰肌醇-3-OH激酶（PI3K）/Akt/mTOR通路。虽然针对EGFR/HER2的单克隆抗体和小分子酪氨酸激酶抑制剂目前正用于乳腺癌治疗，但人们也对靶向细胞可能仍然依赖的关键下游通路有着浓厚兴趣。乳腺癌中这些下游通路的激活可能与对传统内分泌疗法或细胞毒性疗法的耐药性相关，或者实际上与对EGFR/HER2靶向治疗方法缺乏反应有关。法尼基转移酶抑制剂（FTIs）最初是为靶向Ras激活而开发的，尽管其作用机制可能更具非特异性。在乳腺癌中已完成单独使用FTIs或与内分泌或细胞毒性疗法联合使用的试验。PI3K/Akt通路的激活也与对他莫昔芬或雌激素剥夺的耐药性相关，临床前研究表明，mTOR拮抗剂可恢复乳腺癌细胞的内分泌敏感性。芳香化酶抑制剂与mTOR拮抗剂联合使用的随机II/III期试验正在进行中，其样本量已足以检测联合治疗与单独内分泌治疗相比是否能显著延长疾病进展时间。最后，临床前实验正在研究下游药物是否应与上游EGFR/HER2疗法联合使用，以最大程度地阻断垂直信号转导通路。随后需要进行试验，以观察新型信号转导抑制剂的联合使用是否耐受性良好，以及它们如何进一步提高乳腺癌的临床获益。
