Journal
DRUG RESISTANCE UPDATES
Volume 46, Issue -, Pages -Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.drup.2019.100645
Keywords
Cancer; Cancer patients; Clinical multidrug resistance; Genetic variants; Drug-drug interactions; Drug efflux; Drug compartmentalization; Extracellular vesicles; Cell death mechanisms; DNA damage response and repair; Epigenetics; MicroRNAs; Intratumor heterogeneity and dynamics; Stem cell plasticity; Tumor microenvironment; Selection pressures; Acidic environment; Precision medicine
Categories
Funding
- COST (European Cooperation in Science and Technology) [17104]
- Croatian Science Foundation [IP-2016-06-1036]
- Scientific Grant Agency VEGA of Slovak Republic
- Slovak Research and Development Agency [2/0108/17]
- Ministry of Education, Science Research and Sport of Slovak Republic [APVV-17-0384]
- MVTS [34097104]
- Latvian Council of Science Project
- ERA-NET TRANSCAN-2 project PROSCANEXO [lzp-2018/0269]
- Fundacao para a Ciencia e Tecnologia [CEECIND/02300/2017, UID/MULTI/04046/2019, UID/MULTI/00612/2019, PTDC/BIA-BFS/28419/2017, COM/5904/2014]
- Italian Ministry of University and Research
- Foundation for Science and Technology (FCT), Portugal [RBFR12SOQ1001]
- COMPETE-FEDER [UID/NEU/04539/2013, UID/NEU/04539/2019]
- FEDER - Fundo Europeu de Desenvolvimento Regional through COMPETE [POCI-01-0145-FEDER-007440]
- FCT Foundation for Science and Technology [POCI-01-0145-FEDER-030457]
- European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalisation - COMPETE
- Portuguese national funds via FCT - Foundation for Science and Technology [POCI-01-0145-FEDER-016390: CANCEL STEM., NORTE-01-0145-FEDER-000029]
- Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)
- [SFRH/BPD/122871/2016]
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-BFS/28419/2017, SFRH/BPD/122871/2016] Funding Source: FCT
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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 (Le. 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.
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