Overexpression of ABCB1 confers resistance to FLT3 inhibitor FN-1501 in cancer cells: in vitro and in vivo characterization.

ABSTRACT

FN-1501 is a potent FLT3 inhibitor with antitumor activity. A phase 1 trial of FN-1501 monotherapy in patients with advanced solid tumors and R/R AML is in progress. Since one of the primary causes of multidrug resistance (MDR) is the overexpression of ATP-binding cassette superfamily B member 1 (ABCB1), the objective of this study was to investigate the potential relationship between FN-1501 and the ABCB1 transporter. We found ABCB1 overexpressing-cancer cells conferred FN-1501 resistance, which could be reversed by an ABCB1 inhibitor. Molecular docking study revealed that FN-1501 docked the ligand binding site with an affinity score of -9.77 kcal/mol, denoting a strong interaction between FN-1501 and ABCB1. Additionally, the ABCB1 ATPase assay indicated that FN-1501 could significantly stimulate ABCB1 ATPase activity. Furthermore, we observed a similar trend of ABCB1-facilated FN-1501 resistance in tumor-bearing mice model. In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.