An unorthodox AR addiction drives enzalutamide resistance in prostate cancer (RNA-Seq)

ABSTRACT: Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136129 | GEO | 2020/08/20

REPOSITORIES: GEO