Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic.
International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
Int J Mol Sci. 2020 Apr 30;21(9):3157. doi: 10.3390/ijms21093157.
Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients.
酪氨酸激酶抑制剂（TKIs）被越来越多地用于治疗各种恶性肿瘤。虽然它们被设计用于靶向异常的酪氨酸激酶，但它们与癌细胞中多药耐药（MDR）的机制也密切相关。与 MDR 相关的溶质载体（SLC）和 ABC 结合盒（ABC）转运蛋白分别负责 TKI 的摄取和外排。然而，TKI 的作用似乎是双重的，因为它们可以作为这些转运体的底物和/或抑制剂。此外，由于其物理化学性质或通过在溶酶体膜上表达的 ABC 转运体，已经鉴定出几种 TKI 被隔离到溶酶体中。由于 MDR 的发展是癌症治疗中的一个重大关注点，因此阐明 TKI 与 MDR 相关转运体的相互作用以及改善可防止 TKI 扩散到溶酶体的特性非常重要。这些发现不仅有助于避免 MDR，还有助于确定将 TKI 与其他抗癌药物联合使用的可能影响，从而为患者提供更有效的治疗和更少的不良反应。
