Dempke Wolfram C M, Heinemann Volker
University of Munich, University Hospital of Grosshadern, Department of Hematology and Oncology, Industriestrasse 41, D-81245 Munich, Germany.
University of Munich, University Hospital of Grosshadern, Department of Hematology and Oncology, Industriestrasse 41, D-81245 Munich, Germany.
Eur J Cancer. 2009 May;45(7):1117-1128. doi: 10.1016/j.ejca.2008.11.038. Epub 2009 Jan 3.
In an effort to improve the survival of cancer patients, new therapeutic approaches focusing on the molecular mechanisms that mediate tumour cell growth or survival have gained much attention. In particular, EGF-R and VEGF/VEGF-R have been extensively investigated as targets for anti-neoplastic therapy. Agents that selectively target EGF-R, erbB-2, VEGF-R-2 or VEGF have shown promising activity in clinical trials, and several are now approved for use in selected cancer indications. However, all patients ultimately develop resistance to these drugs. Thus, there is a great need to understand how patients become resistant to effective therapies for these cancers since this approach may lead to improvements in therapies that target EGF-R and VEGF/VEGF-R. Pre-clinical studies have begun to shed light on the mechanisms of resistance to anti-angiogenetic drugs and to date four mechanisms of resistance have been identified (1) upregulation of bFGF, (2) overexpression of MMP-9, (3) increased levels of SDF-1alpha and (4) HIF-1alpha-induced recruitment of bone marrow-derived CD45+ myeloid cells. In addition, the molecular mechanisms of resistance to EGF-R modulating agents can be attributed to several general processes: (1) activation of alternative tyrosine kinase inhibitors that bypass the EGF-R pathway (e.g. c-MET and IGF-1R), (2) increased angiogenesis, (3) constitutive activation of downstream mediators (e.g. PTEN and K-ras) and (4) the existence of specific EGF-R mutations. K-ras mutations have been significantly associated with a lack of response to EGF-R tyrosine kinase inhibitors in patients with NSCLC and with a lack of response to cetuximab or to panitumumab in patients with advanced colorectal cancer. The identification of these resistance mechanisms has led to clinical trials using newly designed targeted therapies that can overcome resistance and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for different cancers.
为提高癌症患者的生存率，聚焦介导肿瘤细胞生长或存活的分子机制的新治疗方法备受关注。特别是，表皮生长因子受体（EGF-R）和血管内皮生长因子/血管内皮生长因子受体（VEGF/VEGF-R）已作为抗肿瘤治疗靶点被广泛研究。选择性靶向EGF-R、erbB-2、VEGF-R-2或VEGF的药物在临床试验中显示出有前景的活性，目前有几种已被批准用于特定癌症适应症。然而，所有患者最终都会对这些药物产生耐药性。因此，非常有必要了解患者如何对这些癌症的有效治疗产生耐药性，因为这种方法可能会带来针对EGF-R和VEGF/VEGF-R的治疗改进。临床前研究已开始阐明对抗血管生成药物的耐药机制，迄今为止已确定了四种耐药机制：（1）碱性成纤维细胞生长因子（bFGF）上调，（2）基质金属蛋白酶-9（MMP-9）过表达，（3）基质细胞衍生因子-1α（SDF-1α）水平升高，以及（4）缺氧诱导因子-1α（HIF-1α）诱导的骨髓来源的CD45+髓样细胞募集。此外，对EGF-R调节剂耐药的分子机制可归因于几个一般过程：（1）激活绕过EGF-R途径的替代酪氨酸激酶抑制剂（如c-MET和胰岛素样生长因子-1受体[IGF-1R]），（2）血管生成增加，（3）下游介质的组成性激活（如磷酸酶和张力蛋白同源物[PTEN]和K-ras），以及（4）特定EGF-R突变的存在。K-ras突变与非小细胞肺癌（NSCLC）患者对EGF-R酪氨酸激酶抑制剂缺乏反应以及晚期结直肠癌患者对西妥昔单抗或帕尼单抗缺乏反应显著相关。这些耐药机制的确定已导致使用新设计的靶向疗法进行临床试验，这些疗法可克服耐药性并在实验室研究中显示出前景。正在进行的研究工作可能会继续确定更多的耐药机制，这些发现有望转化为针对不同癌症的有效治疗方法。
