de Klerk Daniel J, Honeywell Richard J, Jansen Gerrit, Peters Godefridus J
Laboratory Medical Oncology, Amsterdam UMC, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Rheumatology and Immunology Center-Location VUmc, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Cancers (Basel). 2018 Dec 10;10(12):503. doi: 10.3390/cancers10120503.
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.
酪氨酸激酶抑制剂是一类针对特定蛋白激酶的化疗药物。这些酪氨酸激酶抑制剂构成了一类相对较新的药物，其作用靶点例如Bcr-Abl、表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGFR）。尽管最初取得了一些成功，但酪氨酸激酶抑制剂在临床上的总体治疗效果喜忧参半。除了靶点突变外，多药耐药性是一个主要障碍，目前尚未开发出临床上有效的应对策略。多药耐药性的主要机制由药物外排转运蛋白介导。此外，越来越多的证据表明，多药耐药性也可能由药物的溶酶体隔离引起，有效地捕获酪氨酸激酶抑制剂并阻止它们到达靶点。溶酶体药物隔离似乎与ATP结合盒转运蛋白协同作用，增加了溶酶体介导隔离的能力。膜外排转运蛋白和溶酶体都是潜在的治疗靶点，它们可以逆转多药耐药性并提高联合治疗中的药物疗效。这篇综述描述了这两种机制，并讨论了一些旨在规避或逆转酪氨酸激酶抑制剂相关多药耐药性的策略。
