Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer.
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer.
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DOI：
10.1038/s41568-022-00454-5
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发表时间：
2022-06
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--
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正常细胞探索多种状态以在发育和自我更新期间遇到的压力以及环境压力（如饥饿，DNA损伤，毒素或感染）中生存。肿瘤细胞选择正常的应激缓解途径以在伴随肿瘤发生、进展、转移和免疫逃避的应激中存活。癌症治疗加重肿瘤细胞应激，并引发快速的非基因组应激缓解过程，其维持细胞活力，因此代表关键的靶向抗性机制。在这篇综述中，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，并描述了利用应激缓解过程的三种不同方法：a）阻断应激缓解以诱导细胞死亡，B）增加应激以诱导细胞灾难和c）利用肿瘤和微环境细胞中的紧急脆弱性。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获得最佳治疗结果，并开发了一个综合框架，以识别和靶向适应性反应和参与压力缓解途径所产生的脆弱性。最后，我们讨论了需要监测多个尺度的适应性反应和翻译的组合疗法，旨在利用适应性反应和缓解压力的途径，以临床。
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. Tumor cells co-opt normal stress mitigation pathways to survive stresses that accompany tumor initiation, progression, metastasis and immune evasion. Cancer therapies accentuate tumor 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 tumor ecosystems, including cancer cells, immune cells, and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: a) interdict stress mitigation to induce cell death, b) increase stress to induce cellular catastrophe and c) exploit emergent vulnerabilities in tumor and microenvironment cells. We review challenges associated with tumor 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.
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DOI：
10.1038/nrc.2016.124
发表时间：
2017-03
期刊：
Nature reviews. Cancer
影响因子：
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作者：
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期刊：
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