Erdafitinib Antagonizes ABCB1-Mediated Multidrug Resistance in Cancer Cells

Abstract

ABCB1 overexpression is known to contribute to multidrug resistance (MDR) in cancers. Therefore, it is critical to find effective drugs to target ABCB1 and overcome MDR. Erdafitinib is a tyrosine kinase inhibitor (TKI) of fibroblast growth factor receptor (FGFR) that is approved by the FDA to treat urothelial carcinoma. Previous studies have demonstrated that some TKIs exhibit MDR reversal effect. In this work, we examined whether erdafitinib could reverse MDR mediated by ABCB1. The results of reversal experiments showed that erdafitinib remarkably reversed ABCB1-mediated MDR without affecting ABCG2-mediated MDR. The results of immunofluorescence and Western blot analysis demonstrated that erdafitinib did not affect the expression of ABCB1 or its cellular localization. Further study revealed that erdafitinib inhibited ABCB1 efflux function leading to increasing intracellular drug accumulation, thereby reversing MDR. Furthermore, ATPase assay indicated that erdafitinib activated the ABCB1 ATPase activity. Docking study suggested that erdafitinib interacted with ABCB1 on the drug-binding sites. In summary, this study demonstrated that erdafitinib can reverse MDR mediated by ABCB1, suggesting that combination of erdafitinib and ABCB1-substrate conventional chemotherapeutic drugs could potentially be used to overcome MDR mediated by ABCB1.

FGFR-TKI resistance in cancer: current status and perspectives

“…For example, ABCB1 has been reported to be a key player in resistance to the multiple-target kinase inhibitor Nintedanib [73,74]. Inhibition of ABCB1 and kinases simultaneously should be a promising strategy for overcoming resistance [75][76][77].…”

Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells

“…Over the last two decades, specific tyrosine kinase inhibitors (TKIs) have been reported to reverse MDR mediate by ABCG2 and ABCB1 transporters. For example, M3814 [20], rociletinib [21], TAE684 [22] and venetoclax [23] significantly attenuate or abolish ABCG2-mediated MDR, whereas tepotinib [24] and erdafitinib [25] overcome MDR mediated by the overexpression of the ABCB1 transporter. ABC transporters can also confer resistance to the TKIs, such as pevonedistat [26], PF-4989216 [27] and tivantinib [28], thereby attenuating their efficacy in cancer cells.…”

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

“…The overexpression of ABCG2 has been found to confer MDR in multiple types of cancers including breast cancer ( Mao and Unadkat, 2015 ), non-small cell lung cancer ( Yoh et al, 2004 ) and acute myelogenous leukemia ( Ross et al, 2000 ). Recently, development of novel ABC transporter inhibitors has achieved promising results in multiple in vitro and in vivo studies, either via synthesizing new small-molecule compounds ( Narayanan et al, 2020 ; Wang et al, 2020c ) or testing the potential reversal effects of FDA-approved drugs ( Dong et al, 2020 ; Feng et al, 2020 ; Yang et al, 2020a ; Wu et al, 2020a ). Instead of designing and synthesizing novel ABCG2 inhibitors, we have focused on the repurposing small-molecule targeted therapeutic agents as ABCG2 modulators as an alternative approach to overcome MDR.…”