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Cancers 2018, 10(12), 503; https://doi.org/10.3390/cancers10120503

Transporter and Lysosomal Mediated (Multi)drug Resistance to Tyrosine Kinase Inhibitors and Potential Strategies to Overcome Resistance

1
Laboratory Medical Oncology, Amsterdam UMC, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
2
Rheumatology and Immunology Center—Location VUmc, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 8 November 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 10 December 2018
(This article belongs to the Special Issue Cancer Chemoresistance)
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PDF [1247 KB, uploaded 10 December 2018]
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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. View Full-Text
Keywords: tyrosine kinase inhibitors; multidrug resistance; ABC transporters; lysosomes tyrosine kinase inhibitors; multidrug resistance; ABC transporters; lysosomes
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De Klerk, D.J.; Honeywell, R.J.; Jansen, G.; Peters, G.J. Transporter and Lysosomal Mediated (Multi)drug Resistance to Tyrosine Kinase Inhibitors and Potential Strategies to Overcome Resistance. Cancers 2018, 10, 503.

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