Sharma Sreenath V, Settleman Jeffrey
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Exp Cell Res. 2009 Feb 15;315(4):557-71. doi: 10.1016/j.yexcr.2008.07.026. Epub 2008 Aug 6.
Lung cancer remains the leading cause of cancer deaths worldwide, and advanced stage disease is largely refractory to conventional chemotherapy. Thus, there is an important need for alternative treatment strategies, and the ErbB proteins have emerged as potentially important therapeutic drug targets in this setting, apparently reflecting a state of "oncogene addiction" in some lung tumors. In this review, we discuss the recent identification of mutations that promote activation of ErbB family proteins in a subset of lung cancers, and the development of selective inhibitors of these proteins that have demonstrated clinical efficacy. We also discuss the problem of drug resistance, which severely limits the clinical utility of such agents, and has prompted intense efforts to better understand molecular mechanisms underlying drug resistance as well as strategies to overcome or prevent such resistance.
肺癌仍然是全球癌症死亡的主要原因，而晚期疾病对传统化疗大多难以奏效。因此，迫切需要替代治疗策略，在这种情况下，表皮生长因子受体（ErbB）蛋白已成为潜在的重要治疗药物靶点，这显然反映了某些肺癌中的“癌基因成瘾”状态。在这篇综述中，我们讨论了最近在一部分肺癌中发现的促进ErbB家族蛋白激活的突变，以及已证明具有临床疗效的这些蛋白的选择性抑制剂的研发情况。我们还讨论了耐药性问题，它严重限制了这类药物的临床应用，并促使人们努力更好地理解耐药性背后的分子机制以及克服或预防这种耐药性的策略。
