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Updated: Jan 6, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
The multi-factorial nature of clinical multidrug resistance in cancer
Yehuda G Assaraf1, Anamaria Brozovic2, Ana Cristina Gonçalves3
1The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200000, Israel.
Abstract:
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.
Insights
Multidrug resistance (MDR) in cancer involves complex host, tumor, and interaction factors. Understanding these mechanisms is key to developing personalized precision medicine to overcome anticancer drug resistance.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Multidrug resistance (MDR) is a major obstacle in curative cancer therapy.
- MDR involves cross-resistance to diverse anticancer drugs.
- Factors contributing to MDR include host genetics, drug interactions, tumor biology, and the tumor microenvironment.
Purpose of the Study:
- To review the multidisciplinary and interdisciplinary features of multidrug resistant (MDR) cancers.
- To consolidate understanding of the diverse molecular mechanisms underlying MDR.
- To highlight the need for precision medicine in treating MDR cancers.
Main Methods:
- Comprehensive literature review of factors contributing to MDR.
- Analysis of host factors, tumor factors, and tumor-host interactions.
- Synthesis of research from COST Action STRATAGEM.
Main Results:
- MDR involves impaired drug uptake, increased drug efflux (e.g., via ATP-binding cassette transporters, extracellular vesicles), altered cell death mechanisms, enhanced DNA repair, and epigenetic changes.
- Intratumor heterogeneity, cancer stem cell plasticity, tumor microenvironment, and acidic pH contribute to MDR.
- Extracellular vesicles play a role in mediating drug resistance through intracellular trait transfer.
Conclusions:
- Deciphering MDR mechanisms is crucial for developing novel precision medicine strategies.
- Personalized and real-time treatment approaches are needed to overcome distinct MDR mechanisms.
- Further research into the complex interplay of factors in MDR cancers will advance therapeutic development.
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