Abstract LB258: ZDHHC20 is a potential target for overcoming ABCB1-mediated multidrug resisance (MDR) in cancer

Abstract

Abstract ABCB1-mediated multidrug resistance (MDR) in cancer cells is an increasingly important cause of anticancer drug treatment failure. The occurrence of MDR in cancer reduces the effectiveness of antitumor drugs, which results in poor quality of life and increased mortality of patients, and creates a heavy burden for the patient's family and society. Hence, the reversal of ABCB1-mediated MDR in cancer is a highly urgent clinical need. Although reversal agents targeting ABCB1 have been developed and partially tested in clinical trials, their main mechanism limits to inhibit the function of ABCB1 efflux pumps, which lacks tumor tissue specificity and has poor clinical effects, and the development of ABCB1-based resistance reversal strategies has entered a bottleneck. ABCB1 mediates tumor MDR through drug efflux and lysosomal segregation, and intervention in the plasma membrane/lysosomal membrane localization of ABCB1 is a potential strategy to reverse drug resistance. Palmitoylation, as a post-translational lipid modification, plays an important role in protein anchoring, transport, and functional regulation, and is highly relevant to human tumors. In the present study, palmitoylation modification was first identified as a key post-translational lipid modification of ABCB1. ABCB1 is palmitoylated in its cytoplasmic domain, which is further stabilized by blocking its ubiquitination, consequently suppressing ABCB1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC20 (DHHC20) as the main acetyltransferase required for the palmitoylation of ABCB1, and show that the inhibition of ABCB1 palmitoylation via 2-bromopalmitate (2-BP), or the silencing of DHHC20, decreases ABCB1 expression and overcomes MDR in vitro as well as in mice bearing SW620/Ad300 resistance cells. Moreover, Cysteine residues C787 was identified as the main palmitoylation cite in human ABCB1. Database and RNAseq analyses revealed that ZDHHC20 is highly expressed in tumor tissues and tumor MDR cells, which makes it a potential tumor tissue-specific target for overcoming ABCB1-mediated MDR in cancer. Our results firstly identified the novel post-translational modification (palmitoylation) of ABCB1 and provide a new research direction and theoretical basis for breaking through the bottleneck of the development of reversal agents for ABCB1-mediated MDR in cancer. Citation Format: Ning Ji, Xin Peng, Yi-nan Liu, Yuqi Yang, Zhe-Sheng Chen, Dexin Kong, Yueguo Li. ZDHHC20 is a potential target for overcoming ABCB1-mediated multidrug resisance (MDR) in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB258.