Abstract 2059: Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition

Abstract

Abstract 1 Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition Ji Hyun Cheon1, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, and Hyung Sik Kim Lab of molecular of toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea A high expression of P-glycoprotein (P-gp) is consistently observed in multidrug resistance (MDR) cancer cells. The purpose of our study was to identify conditions that would increase the sensitivity of P-gp-overexpressing drug-resistant KBV20C cancer cell line. We used commercially available epigenetic library, which includes 128 compounds. Using cellular viability test, we identified that XL019 highly sensitized KBV20C-resistant cells to vincristine treatment. However, XL019-induced sensitization was not observed in vincristine-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Using FACS analysis, western-blot, and annexin V staining, we identified that XL109 sensitized vincristine-treated KBV20C cells via apoptosis and G2 arrest. Furthermore, sensitization potency of XL109 in combination with vincristine was measured in KBV20C cells when comparing with P-gp inhibitor verapamil or another Jak2 inhibitor CEP-33779. We further investigated the mechanisms of XL109 against sensitization of vincristine-treated KBV20C cells. The sensitization mechanism of XL109 was mainly depends on the inhibition of P-gp. In addition, ATPase activity was also conducted to identify as potential role of XL019 in P-gp inhibition. In the docking modeling, XL019 and CEP-33779 showed high binding affinity docking score against ABCB1 receptor protein by -10.590 and -9.104, respectively. Collectively, inhibition of P-gp by XL109 can increase the vincristine-sensitivity in MDR cancer cells through increased apoptosis and G2 arrest. Our findings indicate that Jak2 inhibitor may be a promising target in the treatment of patients resistant to anti-mitotic drug. Note: This abstract was not presented at the meeting. Citation Format: Ji Hyun Cheon, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, Hyung Sik Kim. Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2017-2059