The Role of ABC Multidrug Transporters in Resistance to Targeted Anticancer Kinase Inhibitors

Currently the main treatment option for generalized or metastatic cancer is chemotherapy. Besides conventional chemotherapeutics, small molecule targeted kinase inhibitors (TKIs), which are specifically capable of eliminating key pathways driving cancer growth and metastasis, are also applied in cancer treatment. The hydrophobic TKI molecules need to pass the cell membrane to reach their intracellular targets, and in many cases become substrates of ABC multidrug (MDR) transporters. These large membrane proteins, by using the energy of cellular ATP, actively extrude a wide variety of xeno- and endobiotics from the cells. Tumor cells, and especially cancer stem cells, abuse this promiscuous transporter capacity to protect themselves against therapeutic molecules, including many TKIs. Importantly, the interaction/extrusion by MDR-ABC transporters is not related to the specific, targeted mechanism of TKI action. In this review, we present the key TKIs currently used in cancer therapy, and discuss their interactions with MDR-ABC transporters. We also describe the methods for studying various forms of direct MDR-ABC and TKI interactions, and present a framework for understanding a complex regulation of transporter expression and function by these therapeutic molecules.