文章：

治疗抵抗：癌症靶向治疗的适应性反应所创造的机会

Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer

原文发布日期：2022-03-09

DOI: 10.1038/s41568-022-00454-5

类型: Review Article

开放获取: 否

英文摘要：

Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer therapies accentuate cancer cell stresses and invoke rapid non-genomic stress mitigation processes that maintain cell viability and thus represent key targetable resistance mechanisms. In this Review, we describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment. We review challenges associated with tumour heterogeneity, prioritizing actionable adaptive responses for optimal therapeutic outcomes, and development of an integrative framework to identify and target vulnerabilities that arise from adaptive responses and engagement of stress mitigation pathways. Finally, we discuss the need to monitor adaptive responses across multiple scales and translation of combination therapies designed to take advantage of adaptive responses and stress mitigation pathways to the clinic.

摘要翻译： 

正常细胞通过探索多种状态来应对发育和自我更新过程中的压力，以及诸如饥饿、DNA损伤、毒素或感染等环境压力。癌细胞则利用正常的应激缓解途径，以在肿瘤发生、进展、转移和免疫逃避过程中存活下来。癌症疗法会加剧癌细胞的应激状态，并引发快速的非基因组应激缓解过程，这些过程能维持细胞活力，因此成为关键的可靶向耐药机制。在本篇综述中，我们描述了肿瘤生态系统（包括癌细胞、免疫细胞和基质）适应治疗应激的机制，并阐述了三种利用应激缓解过程的不同方法：（1）阻断应激缓解以诱导细胞死亡；（2）增加应激以引发细胞灾难；（3）利用癌细胞及肿瘤微环境细胞中出现的脆弱性。我们回顾了与肿瘤异质性相关的挑战，优先考虑可操作的适应性反应以实现最佳治疗结果，并开发一个整合性框架以识别和靶向由适应性反应及应激缓解途径参与所产生的脆弱性。最后，我们讨论了监测多尺度适应性反应的必要性，以及将旨在利用适应性反应和应激缓解途径的联合疗法转化为临床实践的需求。

原文链接：

Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer