Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Int J Biochem Cell Biol. 2023 Nov;164:106477. doi: 10.1016/j.biocel.2023.106477. Epub 2023 Oct 18.
The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.
DNA 错配修复途径参与基因组中碱基对错配和插入缺失环的识别、切除和修复。大约 20%的所有癌症都存在错配修复缺陷，导致一种称为微卫星不稳定性的 DNA 损伤。2017 年，免疫检查点抑制剂 Pembrolizumab（一种抗 PD-1 疗法）被批准用于所有不可切除或转移性、错配修复缺陷或具有高微卫星不稳定性的肿瘤，无论组织起源如何。这一具有里程碑意义的批准是首次以无位置依赖的方式批准药物，但不断积累的数据表明，多达 50%的错配修复缺陷肿瘤对治疗有抗药性，而应答者的治疗获益存在巨大差异。已经确定了针对错配修复缺陷癌症的免疫检查点阻断的几种耐药机制，但我们对一部分患者耐药的驱动因素仍缺乏了解。在这篇综述文章中，我们讨论了可能有助于未来对免疫检查点抑制剂治疗进行最佳分层的新兴耐药机制。
