Erlotinib (Tarceva, OSI-774) Antagonizes ATP-Binding Cassette Subfamily B Member 1 and ATP-Binding Cassette Subfamily G Member 2–Mediated Drug Resistance

Abstract

It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)-and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)-mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1-or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E 2 17BG and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [125 I] iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1-and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic. [Cancer Res 2007;67(22):11012-20]

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

“…Oral gefitinib has been reported to increase the oral bioavailability of irinotecan and topotecan (6,13) and to enhance the central nervous system penetration of topotecan in mice (14). Other studies support the hypothesis that gefitinib is a substrate for BCRP (7,15,16) and a functional variant of ABCG2 (BCRP) has recently been associated with greater gefitinib accumulation in humans, thus supporting the hypothesis that BCRP expression and activity may affect the pharmacokinetics of gefitinib (16).…”

“…A recent study indicates that erlotinib reverses ABCB1-and ABCG2-mediated multidrug resistance in cancer cells through direct inhibition of the drug efflux function of MDR1 and BCRP (16). The authors speculate also on a possible transport of erlotinib by MDR1 and BCRP, supported by the publication of Li et al, showing that erlotinib is a substrate of BCRP at relatively low concentrations and a BCRP inhibitor at high concentrations in vitro (17).…”

“…It has recently been reported that erlotinib is transported by BCRP at lower concentrations, whereas at higher concentrations it is an effective BCRP inhibitor (16,17). Therefore, it may be speculated that erlotinib at the higher concentrations used inhibited BCRP and/or P-gp activity, thus reducing its own efflux from the cells.…”

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

“…It would not be surprising if clinical use of ABCG2 inhibitors with novel chemical structures may have unexpected effects due to several problems, such as toxicity or safety and pharmacokinetic uncertainty of the compound. Although most small molecule tyrosine kinase inhibitors (TKI) are competitive or high-affinity substrates of ABCG2 (5), some of them, such as apatinib (6), sunitinib (7), lapatinib (8), erlotinib (9), gefitinib (10), imatinib (11), nilotinib (12), and vandetanib (13), have been reported to be inhibitors or modulators. These TKIs seem to inhibit the function of ABCG2 transporter by directly interacting with this transporter, thereby completely reversing the MDR of cancer cells (14).…”

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

“…Recent studies have shown pharmacological interaction between several clinically important TKIs with the ABC transporters P-gp and BCRP. (20)(21)(22)(23)(24)(25)(26)(27) Regarding pharmacological properties, imatinib, gefitinib, erlotinib, and sunitinib can inhibit the function of ABC transporters and might cause unexpected adverse effects during novel combination chemotherapy with these TKIs and other drugs in early clinical trials.(28-31) Unfortunately, as in our recent report, the pharmacological inhibitory effects of TKIs on ABC transporters are dependent upon the pairings between the transporter protein, the substrate drug, and TKIs.(32) Moreover, genetic polymorphisms of the ABC transporters are associated with modulations in functional transporter activity.(4,33) Therefore, it is difficult to predict the possible pharmacological interactions between TKIs, anticancer drugs, and ABC transporters in individual patient based on the current insufficient evidence.Sunitinib is expected to be examined for use in combination with conventional chemotherapies in various tumor settings. Most recently, sunitinib was shown to antagonize P-gp-and BCRP-mediated drug resistance through direct inhibition of their efflux activities.…”