Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines

Abstract

The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATPbinding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells remains a therapeutic obstacle for scientists and clinicians. Consequently, developing or identifying modulators of ABCB1 and ABCG2 that are suitable for clinical practice is of great importance. Therefore, we have explored the drug repositioning approach to identify candidate modulators of ABCB1 and ABCG2 from tyrosine kinase inhibitors with known pharmacological properties and anticancer activities. In this study, we discovered that avapritinib (BLU-285), a potent, selective, and orally bioavailable tyrosine kinase inhibitor against mutant forms of KIT and platelet-derived growth factor receptor alpha (PDGFRA), attenuates the transport function of both ABCB1 and ABCG2. Moreover, avapritinib restores the chemosensitivity of ABCB1-and ABCG2-overexpressing MDR cancer cells at nontoxic concentrations. These findings were further supported by results of apoptosis induction assays, ATP hydrolysis assays, and docking of avapritinib in the drug-binding pockets of ABCB1 and ABCG2. Altogether, our study highlights an additional action of avapritinib on ABC drug transporters, and a combination of avapritinib with conventional chemotherapy should be further investigated in patients with MDR tumors.

Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

“…ABCB1-mediated ATP hydrolysis was stimulated by erdafitinib in a concentration-dependent manner ( Figure 5), which is consistent with previous reports [29,33,46,56,57] where the ATPase activity of ABCB1 can be stimulated by the presence of a competitive inhibitor in the substrate-binding pocket of ABCB1. Together with the results of erdafitinib stimulating ABCB1 ATPase activity, the in silico docking analysis of erdafitinib binding to ABCB1 in the inward-open conformation ( Figure 6) supports the notion that erdafitinib interacts with several amino acid residues within the transmembrane domain of ABCB1 and attenuates the binding of another drug substrate by direct competition (Figure 7).…”

“…More significantly, results of erdafitinib inhibiting the drug efflux function of ABCB1 ( Figure 2 ) and improving the susceptibility of KB-V-1 cells to drug-induced apoptosis ( Figure 4 ) indicate that erdafitinib reverses ABCB1-mediated multidrug resistance by restoring the cytotoxicity of ABCB1 substrate anticancer drugs in these multidrug-resistant cancer cells. Moreover, ABCB1-mediated ATP hydrolysis was stimulated by erdafitinib in a concentration-dependent manner ( Figure 5 ), which is consistent with previous reports [ 29 , 33 , 46 , 56 , 57 ] where the ATPase activity of ABCB1 can be stimulated by the presence of a competitive inhibitor in the substrate-binding pocket of ABCB1. Together with the results of erdafitinib stimulating ABCB1 ATPase activity, the in silico docking analysis of erdafitinib binding to ABCB1 in the inward-open conformation ( Figure 6 ) supports the notion that erdafitinib interacts with several amino acid residues within the transmembrane domain of ABCB1 and attenuates the binding of another drug substrate by direct competition ( Figure 7 ).…”

“…For instance, previous clinical trials of tariquidar (XR9576) in combination with vinorelbine (NCT00042315) or paclitaxel (NCT00042302) to treat non-small cell lung cancer (NSCLC) were terminated prematurely due to toxicity. In contrast, recent studies have demonstrated that several FDA-approved therapeutic agents such as osimertinib and midostaurin exhibited an inhibitory effect on ABCB1-mediated drug efflux, thus resensitizing ABCB1-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents [29,[44][45][46]. Moreover, the advantage of using combination therapy against multidrug-resistant cancers was demonstrated in a recent phase I study of concomitant administration of doxorubicin with nilotinib as a co-adjuvant treatment in sarcoma patients [47].…”

Erdafitinib Antagonizes ABCB1-Mediated Multidrug Resistance in Cancer Cells

“…Therefore, ATPase assay of ABCB1 was performed to test if erdafitinib could alter the ATPase activity of ABCB1. Our results showed that erdafitinib concentration-dependently activated the ABCB1-associated ATPase, consisting with previous studies (42,43). Some ABC transporter substrate drugs can act as competitive inhibitors that bind to a distinct substrate-binding site and inhibit the efflux of a particular class of substrates (44).…”

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

“…Another possibility is that some substrate inhibitors can interact with ABCG2 on sites other than the substrate-binding sites and cause conformational changes in the binding pocket which allosterically affect the transportation of some substrates (59). It should be noted that, although several ABCG2 inhibitors were identified as substrates through ATPase assay, overexpression of ABCG2 does not necessarily confer drug resistance to these inhibitors (49,54,(60)(61)(62). Hitherto, the detailed mechanism of this inhibitory effect remained inconclusive and desire further exploration.…”