The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200000, Israel.
Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000, Zagreb, Croatia.
Drug Resist Updat. 2019 Sep;46:100645. doi: 10.1016/j.drup.2019.100645. Epub 2019 Sep 17.
Curative cancer therapy remains a major challenge particularly in cancers displaying multidrug resistance (MDR). The MDR phenotype is characterized by cross-resistance to a wide array of anticancer drugs harboring distinct structures and mechanisms of action. The multiple factors involved in mediating MDR may include host factors, tumor factors as well as tumor-host interactions. Among the host factors are genetic variants and drug-drug interactions. The plethora of tumor factors involves decreased drug uptake primarily via impaired influx transporters, increased drug efflux predominantly due to the overexpression of MDR efflux transporters of the ATP-binding cassette superfamily or due to drug efflux mediated by extracellular vesicles (EVs) or drug-loaded lysosomes undergoing exocytosis, deregulation of cell death mechanisms (i.e. anti-apoptotic modalities), enhanced DNA damage repair, epigenetic alterations and/or deregulation of microRNAs. The intratumor heterogeneity and dynamics, along with cancer stem cell plasticity, are important tumor factors. Among the tumor-host interactions are the role of the tumor microenvironment, selective pressure of various stressor conditions and agents, acidic pH and the intracellular transfer of traits mediated by EVs. The involvement of these diverse factors in MDR, highlights the need for precision medicine and real-time personalized treatments of individual cancer patients. In this review, written by a group of researchers from COST Action STRATAGEM "New diagnostic and therapeutic tools against multidrug resistant tumors", we aim to bring together these multidisciplinary and interdisciplinary features of MDR cancers. Importantly, it is becoming increasingly clear that deciphering the molecular mechanisms underlying anticancer drug resistance, will pave the way towards the development of novel precision medicine treatment modalities that are able to surmount distinct and well-defined mechanisms of anticancer drug resistance.
癌症的治疗仍然是一个主要的挑战，尤其是在表现出多药耐药性（MDR）的癌症中。MDR 表型的特征是对具有不同结构和作用机制的广泛抗癌药物交叉耐药。介导 MDR 的多种因素可能包括宿主因素、肿瘤因素以及肿瘤-宿主相互作用。宿主因素包括遗传变异和药物-药物相互作用。大量的肿瘤因素涉及药物摄取减少，主要是通过受损的流入转运体；药物外排增加，主要是由于 ABC 超家族的 MDR 外排转运体过度表达，或通过细胞外囊泡（EVs）介导的药物外排或正在进行胞吐作用的载药溶酶体，细胞死亡机制的失调（即抗凋亡方式），增强的 DNA 损伤修复，表观遗传改变和/或 microRNAs 的失调。肿瘤内异质性和动态性以及癌症干细胞可塑性是重要的肿瘤因素。肿瘤-宿主相互作用包括肿瘤微环境的作用、各种应激源和药物的选择压力、酸性 pH 值以及 EVs 介导的细胞内性状转移。这些不同因素在 MDR 中的参与，突出了精准医学和个体化癌症患者实时治疗的必要性。在这篇由 COST 行动 STRATAGEM“针对多药耐药肿瘤的新诊断和治疗工具”的研究人员撰写的综述中，我们旨在汇集 MDR 癌症的这些多学科和跨学科特征。重要的是，越来越明显的是，阐明抗癌药物耐药性的分子机制将为开发能够克服不同且明确的抗癌药物耐药机制的新型精准医学治疗方法铺平道路。
