Ikediobi O N
Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, CA 94118, USA.
Pharmacogenomics J. 2008 Oct;8(5):305-14. doi: 10.1038/tpj.2008.8. Epub 2008 Aug 5.
Many of the initial examples of the clinical utility of pharmacogenetics were elucidated in the field of oncology. Those examples were largely based on the existence of germline genetic variation that influences the metabolism of cytotoxic drugs. However, with the development of kinase inhibitors, drugs designed to preferentially target altered proteins driving oncogenesis, pharmacogenetics in cancer has shifted to understanding the somatic differences that determine response to these targeted agents. It is becoming increasingly clear that understanding the molecular genetics of cancer will lead to the further development of targeted therapeutics. Therefore, it is imperative that pharmacogenomics researchers understand the motivations and challenges of developing targeted therapies to treat cancer as a paradigm for personalized medicine. However, much of the discussion in the pharmacogenomics community in cancer is still largely focused on the germline variants as predictors of drug toxicity. In light of that fact, this review presents a detailed discussion of the development of commonly used targeted therapies for the treatment of hematological and solid tumors, the somatic mutations that determine response to those therapies, and the mechanisms of drug resistance.
药物遗传学临床应用的许多初始实例是在肿瘤学领域阐明的。这些实例很大程度上基于影响细胞毒性药物代谢的种系基因变异的存在。然而，随着激酶抑制剂的发展，这类旨在优先靶向驱动肿瘤发生的改变蛋白的药物，癌症领域的药物遗传学已转向了解决定对这些靶向药物反应的体细胞差异。越来越清楚的是，了解癌症的分子遗传学将推动靶向治疗的进一步发展。因此，药物基因组学研究人员必须了解开发靶向疗法以治疗癌症作为个性化医学范例的动机和挑战。然而，癌症药物基因组学领域的许多讨论仍主要集中在种系变异作为药物毒性的预测指标上。鉴于这一事实，本综述详细讨论了用于治疗血液系统肿瘤和实体瘤的常用靶向疗法的发展、决定对这些疗法反应的体细胞突变以及耐药机制。
