Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.
Cancer Res. 2011 Nov 15;71(22):7071-9. doi: 10.1158/0008-5472.CAN-11-0128. Epub 2011 Nov 8.
There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (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.
目前，人们对表皮生长因子受体 (EGFR) 抑制剂获得性耐药的机制非常感兴趣，这些抑制剂目前广泛用于治疗多种常见的人类癌症。为了研究这些机制，我们从非小细胞肺癌细胞中建立了 EGFR 抑制剂耐药克隆。比较分析表明，EGFR 抑制剂获得性耐药与 p53 的缺失和对辐射的交叉耐药一致。为了研究 p53 的作用，我们首先在敏感亲本细胞中敲低 p53，发现对 EGFR 抑制剂和辐射的敏感性降低。相反，在 EGFR 抑制剂耐药细胞中恢复功能性 p53 足以使其在体外和体内重新对 EGFR 抑制剂或辐射敏感。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 EGFR 抑制剂获得性耐药的发展中起着核心作用，并促使考虑在未来将 EGFR 抑制剂与辐射联合应用的临床试验中应用 p53 恢复策略。
