Abstract 1126: Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate cancer

Abstract

Abstract Prostate cancer is the second-leading cause of cancer-related mortality among men in the United States. Androgen receptor (AR) signaling is dominant survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) through medical or surgical castration is the mainstay treatment for prostate cancer patients. Enzalutamide (Xtandi®), a second generation antiandrogen, is frequently prescribed for use in this clinical setting. Patient's response to this medication is usually temporary, and prolong treatment results in the emergence of drug resistance. A better understanding of molecular mechanism and its association with enzalutamide resistance will facilitate circumventing this problem. We employed next generation sequencing (NGS) and compared the transcriptomic profile of paired enzalutamide-sensitive and resistant human prostate cancer LNCaP and C4-2B cells for identification of genes involved in drug resistance along with in silico analysis. NGS data identified 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells compared to their parental counterparts. A subset of differentially expressed genes in both cell lines were validated at transcript level by qRT-PCR. Data analysis performed by IPA/i-pathway revealed metabolic signaling as predominantly overrepresented pathway and membrane transporters including solute carrier proteins, ATP-binding cassette transporters and other metabolizing enzymes as the most prominent genes dysregulated during metabolic reprogramming in both resistant cell lines. RNA-Seq data of resistant LNCaP cells demonstrate predominance of solute carrier genes, in particular, SLC12A5, SLC25A17 and SLC27A6, during metabolic reprogramming and in the development of drug resistance. Upregulation of these genes were associated with an increase in stemness; higher uptake of lactic/citric acid and lower glucose intake by the resistant cells. Our data suggest predominance of solute carrier genes (SLCs) during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment. SLCs are important in cellular uptake of nutrients and drug absorption, thus could play a significant role in the emergence of drug-resistant phenotype, designating SLC genes as potentially attractive therapeutic targets. Citation Format: Shiv Shankar Verma, Eswar Shankar, Ricky Chan, Sanjay Gupta. Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1126.