Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.
Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.
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DOI：
10.1371/journal.pone.0000810
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发表时间：
2007-08-29
期刊：
影响因子：
3.7
通讯作者：
Pao W
中科院分区：
文献类型：
--
作者：
Regales L;Balak MN;Gong Y;Politi K;Sawai A;Le C;Koutcher JA;Solit DB;Rosen N;Zakowski MF;Pao W
EGFR T790M突变在人EGFR突变肺腺癌中赋予对激酶抑制剂的获得性耐药性，在治疗前偶尔检测到，并可能赋予肺癌的遗传易感性。为了进一步研究其在肺肿瘤发生中的作用，我们在II型肺细胞中培养了EGFRT790M单独或与药物敏感的L858R突变一起诱导表达的小鼠。这两种转基因细胞系都发展为肺腺癌，需要突变的EGFR来维持肿瘤，但对EGFR激酶抑制剂具有耐药性。EGFRL858R+ t790m驱动的肿瘤被hsp90抑制瞬时靶向。值得注意的是，表达egfrt790m的动物比携带EGFRL858R+ t790m的小鼠发生肿瘤的潜伏期更长，并且没有额外的激酶结构域突变。这些新的突变型egfr依赖性肺腺癌小鼠模型为临床观察提供了见解。这些模型也应该有助于开发针对单独携带EGFRT790M或与药物敏感的EGFR激酶结构域突变联合携带EGFRT790M的肺癌患者的改进疗法。
The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFRL858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFRT790M-expressing animals develop tumors with longer latency than EGFRL858R+T790M-bearing mice and in the absence of additional kinase domain mutations. These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.
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DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
影响因子：
30.8
作者：
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通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
15.8
作者：
Greulich H;Chen TH;Feng W;Jänne PA;Alvarez JV;Zappaterra M;Bulmer SE;Frank DA;Hahn WC;Sellers WR;Meyerson M
通讯作者：
Meyerson M