Original ArticleTyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

- Tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, directly inhibits the transport function of ABCG2.
- Tyrphostin is ABCG2 specific.
- Tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity of ABCG2-overexpressing multidrug-resistant cancer cells.
- Docking analysis indicates tyrphostin RG14620 binds to the drug-binding pocket of ABCG2.
- Tyrphostin RG14620 is a potent and selective modulator of ABCG2 that is useful to overcome chemoresistance in patients with drug-resistant tumors.

The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.