Abstract 3010: VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport in vitro and in vivo

The emergence of multidrug resistance (MDR) to chemotherapeutic drugs continues to be a major problem in the treatment of cancer. Drug resistance, either intrinsic or extrinsic is responsible for the recurrence of cancer related deaths. Understanding the drug resistant mechanisms of cancer is necessary for developing an effective treatment. ATP-binding cassette transporters are the integral transmembrane proteins which play a role in the expulsion of chemotherapeutic drugs, make the MDR more complicated. Breast cancer resistance protein (BCRP/ABCG2) is one among the MDR transporters with a wide range of substrates and overexpressed in various kinds of cancers like breast, colon, ovarian and lung cancers. An analysis of various new compounds leads to the discovery of VKNG-1 that selectively inhibits ABCG2 transporter and reverses the resistance to chemotherapeutic drugs both in vitro and in vivo. VKNG-1 selectively causes the ABCG2 inhibition and sensitizes the ABCG2 overexpressing resistant cells to the substrate anti-cancer drugs. The mechanism of action of VKNG-1 is its ability to prevent the efflux function of ABCG2 and thereby increases the intracellular accumulation of substrate drugs. In addition, there was a decrease in the expression of ABCG2 at both mRNA and protein level, but the protein translocation did not happen in the presence of VKNG-1. The induced-fit docking studies suggest the existence of strong interactions between VKNG-1and BCRP protein. In addition, VKNG-1 maintains the anti-cancer effect of irinotecan in ABCG2 overexpressing tumor xenografts and combination of VKNG-1 and irinotecan greatly inhibited the growth of S1-M1-80 resistant tumors. These results suggest that potent and selective action of VKNG-1 makes it as a promising treatment option in overcoming drug resistance in cancer. Citation Format: Silpa Narayanan, Nehaben A. Gujarati, Qiuxu Teng, Jingquan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh Jaganna Chintalapati, Vijaya L. Korlipara, Zhe-Sheng Chen. VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3010.