靶向癌症的 DNA 损伤反应。

Targeting the DNA Damage Response in Cancer.

机构信息

Senior Principal Scientist, Head of the DNA Damage Response Biology Area, Oncology IMED, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom.

出版信息

Mol Cell. 2015 Nov 19;60(4):547-60. doi: 10.1016/j.molcel.2015.10.040.

DOI:10.1016/j.molcel.2015.10.040

PMID:26590714

Abstract

An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future.

摘要

癌症的一个基本特征是基因组不稳定性，这与更容易积累 DNA 损伤有关。放疗和 DNA 损伤化疗等癌症的历史治疗方法就是基于这一原理，但同时也会对正常组织造成严重的附带损伤和不必要的副作用。基于抑制癌症中 DNA 损伤反应 (DDR) 的靶向治疗为缺乏特定 DDR 功能的肿瘤患者提供了更精确的治疗方案，从而有可能获得更大的治疗窗口。最近批准的奥拉帕利（Lynparza），即聚（ADP-核糖）聚合酶（PARP）抑制剂，用于治疗携带 BRCA1 或 BRCA2 突变的肿瘤，这是基于该原理的第一种药物，利用了肿瘤形成的潜在原因，也代表了一个致命弱点。本文重点介绍了靶向癌症 DDR 的不同概念，以及这如何为未来基于 DDR 的治疗提供重要机会。