p53 modulates acquired resistance to EGFR inhibitors and radiation.
p53 modulates acquired resistance to EGFR inhibitors and radiation.
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DOI：
10.1158/0008-5472.can-11-0128
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发表时间：
2011-11-15
期刊：
影响因子：
11.2
通讯作者：
Harari PM
中科院分区：
文献类型：
--
作者：
Huang S;Benavente S;Armstrong EA;Li C;Wheeler DL;Harari PM
目前，人们对EGFR抑制剂的获得性耐药机制非常感兴趣，这些药物目前被广泛用于治疗各种常见的人类癌症。为了研究这些机制，我们从非小细胞肺癌细胞中建立了耐EGFR抑制剂的克隆。一项比较分析显示，对EGFR抑制剂的获得性耐药与p53的丢失和对辐射的交叉耐药一致相关。为了研究P53的作用，我们首先在敏感的亲代细胞中击倒了P53，发现对EGFR抑制剂和辐射的敏感性都降低了。相反，在EGFR抑制剂耐药细胞中恢复功能性P53足以使它们在体外和体内对EGFR抑制剂或辐射重新敏感。进一步的研究表明，P53可能通过诱导细胞周期停滞、细胞凋亡和DNA损伤修复来增强对EGFR抑制剂和辐射的敏感性。综上所述，这些发现表明P53在对EGFR抑制剂的获得性耐药性的发展中起核心作用，并促使考虑在未来结合EGFR抑制剂和辐射的临床试验中应用P53修复策略。
There is presently great interest in mechanisms of acquired resistance to EGFR inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms we established EGFR inhibitor resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell cycle arrest, apoptosis and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.