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

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Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV

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

Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4.

PubMed ID

31117741 [ View in PubMed

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Abstract

The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATP-binding 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.

DrugBank Data that Cites this Article

Drugs

Avapritinib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Avapritinib	Mast/stem cell growth factor receptor Kit	Protein	Humans	Unknown	Inhibitor	Details
Avapritinib	Platelet derived growth factor receptor alpha	Protein	Humans	Unknown	Inhibitor	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Avapritinib	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor Modulator	Details
Avapritinib	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor Modulator	Details