Abstract
Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite some initial successes, the overall therapeutic benefit of tyrosine kinase inhibitors in the clinic has been mixed. Next to mutations in the target, multidrug resistance is a major obstacle for which still no clinically effective strategies have been developed. Major mechanisms of multidrug resistance are mediated by drug efflux transporter proteins. Moreover, there is accumulating evidence that multidrug resistance can also be caused by lysosomal sequestration of drugs, effectively trapping tyrosine kinase inhibitors and preventing them from reaching their target. Lysosomal drug sequestration seems to work together with ATP-binding cassette transporters, increasing the capacity of lysosomes to mediate sequestration. Both membrane efflux transporter proteins and lysosomes present potential therapeutic targets that could reverse multidrug resistance and increase drug efficacy in combination therapy. This review describes both mechanisms and discusses a number of proposed strategies to circumvent or reverse tyrosine kinase inhibitor-related multidrug resistance.
Highlights
Tyrosine kinase inhibitors (TKI) represent a class of chemotherapeutic drugs that target protein kinases as a means of disrupting cell division and other cellular processes that contribute to tumour cell progression and proliferation
ABCB1 and ABCG2 are expressed in Polymorphisms within the ABCB1 have lumen presented conflicting outcomes there may cells of relevant tissues such asgene intestinal and with blood-brain barriers, wherealthough they transport be a role for drugback response and adverse effectswhile
Other regulatory pathways involved in the induction of ATP-binding cassette (ABC) transporters include the MED1, which has been linked with drug resistant and aggressive phenotypes, and MEF-1, a regulator of P-gp expression, which has been detected in HL60 drug-resistant leukemia cell line [120,121]
Summary
Tyrosine kinase inhibitors (TKI) represent a class of chemotherapeutic drugs that target protein kinases as a means of disrupting cell division and other cellular processes that contribute to tumour cell progression and proliferation. Cancers 2018, 10, 503 resistance can limit the initial response or prevent drugs reaching their targets due to hurdles negatively influencing the pharmacology of the drug, such as patient specific metabolism, rapid clearance or not being able to pass through membranes of cancer cells or other barriers like the blood brain barrier [11]. Cancer cells, especially those resistant against multiple drugs, remain a major obstacle in effective cancer therapy. This review provides an overview of multidrug resistance for TKIs with specific focus on the role of influx/efflux transporter proteins and lysosomal drug sequestration, including possible modalities of circumventing drug resistance
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