Identification of drivers and therapeutic vulnerabilities in anti-androgen resistant prostate cancer cells

Inhibition of the androgen receptor (AR) by anti-androgens is the standard treatment for castration resistant prostate cancer (CRPC), but it inevitably leads to the development of resistance. We generated two multi anti-androgen resistant cell-line models by treatment of LNCaP cells with enzalutamide (ResA) and RD-162 (ResB). Both cell-lines have an AR independent, non-neuroendocrine phenotype. To identify the resistance mechanisms we performed RNASeq analysis. To this end, the three cell-lines were plated in medium with 5% dextran-coated charcoal (DCC) treated FCS at a density of 1 million cells/well in 6-well plates. After 24 hours of steroid starvation the cells were treated with 10 nM of the androgen dihydrotestosterone (DHT), 10 µM of the anti-androgen enzalutamide, a combination of the two, or vehicle (DMSO) for 18 hours. Examination of the gene expression profile in LNCaP and the two LNCaP derived anti-androgen resistant cell-lines ResA and ResB in androgen-depleted conditions and in presence of DHT and enzalutamide.