Davies Michael, Hennessy Bryan, Mills Gordon B
University of Texas--M D Anderson Cancer Center, Department of Medical Oncology, 1515 Holcombe Blvd, Unit 10, Houston, TX 77030, USA.
Expert Opin Pharmacother. 2006 Nov;7(16):2243-61. doi: 10.1517/14656566.7.16.2243.
The treatment of cancer is rapidly changing, with an increasing focus on converting our improved understanding of the molecular basis of disease into clinical benefit for patients. Protein kinases that are mutated in cancer represent attractive targets, as they may result in cellular dependency on the mutant kinase or its associated pathway for survival, a condition known as 'oncogene addiction'. Early clinical experiences have demonstrated dramatic clinical benefit of targeting oncogenic mutations in diseases that have been largely resistant to traditional cytotoxic chemotherapy. Further, mutational activation of kinases can indicate which patients are likely to respond to targeted therapeutics. However, these experiences have also illuminated a number of critical challenges that will have to be addressed in the development of effective drugs across different cancers, to fully realise the potential of individualised molecular therapy. This review utilises examples of genetic activation of kinases to illustrate many of the lessons learned, as well as those yet to be implemented.
癌症治疗正在迅速变化，越来越注重将我们对疾病分子基础的深入理解转化为对患者的临床益处。在癌症中发生突变的蛋白激酶是有吸引力的靶点，因为它们可能导致细胞对突变激酶或其相关通路产生生存依赖，这种情况被称为“癌基因成瘾”。早期临床经验表明，在对传统细胞毒性化疗大多耐药的疾病中，靶向致癌突变可带来显著的临床益处。此外，激酶的突变激活可以表明哪些患者可能对靶向治疗有反应。然而，这些经验也揭示了一些关键挑战，在开发针对不同癌症的有效药物时必须加以解决，以充分实现个体化分子治疗的潜力。本综述利用激酶基因激活的实例来说明许多已吸取的经验教训，以及尚未实施的经验教训。
