Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, UK.
Nat Biotechnol. 2012 Jul 10;30(7):679-92. doi: 10.1038/nbt.2284.
Over the past decade, whole genome sequencing and other 'omics' technologies have defined pathogenic driver mutations to which tumor cells are addicted. Such addictions, synthetic lethalities and other tumor vulnerabilities have yielded novel targets for a new generation of cancer drugs to treat discrete, genetically defined patient subgroups. This personalized cancer medicine strategy could eventually replace the conventional one-size-fits-all cytotoxic chemotherapy approach. However, the extraordinary intratumor genetic heterogeneity in cancers revealed by deep sequencing explains why de novo and acquired resistance arise with molecularly targeted drugs and cytotoxic chemotherapy, limiting their utility. One solution to the enduring challenge of polygenic cancer drug resistance is rational combinatorial targeted therapy.
在过去的十年中，全基因组测序和其他“组学”技术已经确定了肿瘤细胞成瘾的致病驱动突变。这些成瘾、合成致死性和其他肿瘤脆弱性为新一代癌症药物提供了新的靶点，以治疗具有明确遗传定义的患者亚群。这种个性化癌症治疗策略最终可能会取代传统的一刀切的细胞毒性化疗方法。然而，深度测序揭示的癌症中非同寻常的肿瘤内遗传异质性解释了为什么新出现的和获得性的耐药性会随着分子靶向药物和细胞毒性化疗而出现，限制了它们的应用。解决多基因癌症药物耐药性这一持久挑战的方法之一是合理的组合靶向治疗。
