Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors.
Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors.
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DOI：
10.1016/j.ctrv.2011.01.003
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发表时间：
2011-10
影响因子：
11.8
通讯作者：
Wang, Yisong
中科院分区：
文献类型：
--
作者：
Giaccone, Giuseppe;Wang, Yisong
关键词：
第一代表皮生长因子受体酪氨酸激酶抑制剂Erlotinib和Gefitinib已被纳入晚期非小细胞肺癌患者的治疗范例。这些药物对肿瘤中含有激活表皮生长因子受体突变的一部分患者特别有效。然而，大多数患者对这些酪氨酸激酶抑制剂没有反应，而那些有反应的患者最终会获得耐药性，这种耐药性通常是由继发性表皮生长因子受体突变(如T790M)、间充质-上皮转化因子扩增或其他信号通路的激活引起的。对于肿瘤具有野生型表皮生长因子受体的患者，有几种已知的初始耐药机制(如Kirsten鼠肉瘤病毒癌基因同源突变)，但这些机制并不能解释所有病例，这表明未知的机制也起到了作用。为了潜在地克服耐药性的问题，正在开发下一代酪氨酸激酶抑制剂，它们不可逆转地阻断多个表皮生长因子受体家族成员(例如，阿法替尼[BIBW2992]，PF-00299804)和/或血管内皮生长因子受体通路(例如，BMS-690514，XL647)。此外，阻断表皮生长因子受体下游平行信号通路或信号分子的药物，如胰岛素样生长因子-1受体和哺乳动物靶标雷帕霉素，正在接受临床评估。由于耐药性似乎是多形性的，药物或多靶点药物的组合可能在规避耐药性方面更有效。
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (eg, T790M), mesenchymal-epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (eg, Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (eg, afatinib [BIBW 2992], PF-00299804) and/or vascular endothelial growth factor receptor pathways (eg, BMS-690514, XL647). In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance.
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DOI：
10.1016/s1470-2045(10)70132-7
发表时间：
2010-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Herbst RS;Sun Y;Eberhardt WE;Germonpré P;Saijo N;Zhou C;Wang J;Li L;Kabbinavar F;Ichinose Y;Qin S;Zhang L;Biesma B;Heymach JV;Langmuir P;Kennedy SJ;Tada H;Johnson BE
通讯作者：
Johnson BE
影响因子：
45.3
作者：
Eberhard, DA;Johnson, BE;Hillan, KJ
通讯作者：
Hillan, KJ
影响因子：
5.7
作者：
Gonzales, Andrea J.;Hook, Kenneth E.;Vincent, Patrick W.
通讯作者：
Vincent, Patrick W.
影响因子：
5.7
作者：
Godin-Heymann, Nadia;LlIkus, Lindsey;Haber, Daniel A.
通讯作者：
Haber, Daniel A.
影响因子：
11.2
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
通讯作者：
Janne, Pasi A.