Journal
MOLECULAR PHARMACEUTICS
Volume 16, Issue 7, Pages 3040-3052Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.9b00274
Keywords
chemoresistance; combination chemotherapy with BLU-285; modulators; P-glycoprotein; breast cancer resistance protein
Funding
- Chang Gung Medical Research Program [BMRPC17, CMRPD1G0113]
- Ministry of Science and Technology of Taiwan [MOST-107-2320-B-182-017]
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute
- NATIONAL CANCER INSTITUTE [ZIABC010030] Funding Source: NIH RePORTER
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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.
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