De Conti Giulia, Dias Matheus Henrique, Bernards René
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Cancers (Basel). 2021 Mar 5;13(5):1118. doi: 10.3390/cancers13051118.
Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.
为耐药性癌症设计特定疗法可谓是癌症治疗中的终极挑战。尽管人们十分重视对导致耐药性的基因改变的研究，但对于耐药性发展早期阶段起作用的非基因适应机制却知之甚少。药物耐受持久性细胞被认为是这一过程中的关键因素。这些细胞被认为经历了非基因适应，从而能够在药物存在的情况下存活，完全耐药的细胞可能由此产生。这种初始适应通常涉及应激反应程序的启动，以维持癌细胞的活力。在这篇综述中，我们讨论了药物耐受癌症表型的本质以及所涉及的非基因适应。我们还讨论了恶性细胞如何利用体内平衡应激反应途径来减轻这种适应的内在代价。最后，我们讨论了这些适应会带来哪些脆弱性，以及如何在治疗中利用这些脆弱性。
