Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

Abstract

Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

“…First-generation ALK inhibitor crizotinib was shown to enhance the efficacy of doxorubicin and paclitaxel via ABCB1 inhibition in vitro and in vivo, respectively [35]. In addition, second-generation ALK inhibitors ceritinib and alectinib were both described as dual ABCB1 and ABCG2 inhibitors able to potentiate anticancer effects of chemotherapeutic drugs, which are substrates of these transporters [36,37]. Noteworthy, these properties are not limited only to ALK inhibitors but were observed also in TKIs hitting other targets, such as epidermal growth factor receptor (EGFR) inhibitor gefitinib, vascular endothelial growth factor receptor (VEGFR) inhibitor sorafenib and several others [19,20].…”

Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells

“…Alectinib, an inhibitor of ALK, was approved by FDA for the treatment of NSCLC in 2015. In order to investigate whether alectinib could reverse ABCB1-mediated MDR in ex vivo, Yang et al collected ABCB1-overexpressing bone marrow samples from 4 resistance patients with AML or CML, and found that alectinib potently resensitized these drug resistant samples to Rhodamine 123, doxurubin and verapamil through MTT assays analysis [ 90 ], suggesting alectinib is able to reverse ABCB1-mediated MDR phenotype in primary leukemia cell.…”

Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

“…It is conceivable that TKIs also bind to ATP binding site of ABC transporter. In recent years, we have demonstrated that a number of TKIs, including lapatinib [ 12 ], alectinib [ 13 ] and apatinib [ 14 ], can be used to potentiate the efficacy of anticancer drugs in MDR cancer cells by inhibiting ABC transporters. The line of research suggested that TKIs may be developed into useful agents for circumventing MDR.…”