Abstract 980: PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Multidrug resistance (MDR) through overexpression of ATP-binding cassette (ABC) transporters has long evaded chemotherapy in cancer patients. Specific tyrosine kinase inhibitors (TKIs) were recently reported to modulate these ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. Here, we report for the first time, PD173074 an inhibitor of the fibroblast growth factor receptor (FGFR), to selectively inhibit ABC subfamily B member 1 (ABCB1/P-glycoprotein) transporter. PD173074 significantly sensitized both ABCB1 transfected and drug selected cell lines overexpressing this transporter to anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific, as no significant interaction was detected with other ABC transporters such as ABCC1, and ABCG2. The observed inhibition was primarily due to the decreased active efflux of [3H]-paclitaxel in ABCB1 overexpressing cells. However, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 μM PD173074 for up to 3 days thereby suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit the photolabeling of ABCB1 with [125I]-Iodoarylazidoprazosin (IAAP) showing that it binds at a site different from that of IAAP in the drug-binding pocket. In conclusion, PD173074 could selectively reverse ABCB1-mediated MDR by directly blocking the efflux function of ABCB1. Citation Format: Atish S. Patel, Amit Tiwari, Eduardo Chufan, Satyakam Singh, Kamlesh Sodani, Nagaraju Anreddy, Tanaji Talele, Suresh Ambudkar, Ralph Stephani, Zhe-Sheng Chen. PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 980. doi:10.1158/1538-7445.AM2013-980