The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non-neuroendocrine androgen receptor-low castration resistant prostate cancer (AR low CRPC) is increasing in occurrence amongst patients and is uniformly fatal. The mechanisms that promote this phenotype remain poorly understood. Through molecular studies of murine and human models of AR low CRPC, we have identified a new functional interface between the androgen receptor and the translation initiation complex inhibitor 4EBP1. AR directly regulates 4EBP1 expression which translationally represses eIF4F complex formation and a pro-proliferation program. In the context of AR low prostate cancer, de-repression of translation initiation drives the aberrant expression of the pro-proliferation regulon which fuels uncontrolled cell growth. Genetic and pharmacologic inhibition of the downstream eIF4F translation initiation complex reverses the proliferation phenotype in vitro and in vivo. These findings reveal a new previously unrecognized druggable nexus which functionally link the processes of mRNA transcription and translation initiation in a rapidly emerging class of advanced lethal prostate cancer Overall design: Androgen receptor low prostate cancer has been on the rise with the advent of potent androgen receptor and androgen biosynthesis inhibitors and is uniformly fatal. The mechanisms underlying disease progression remains unresolved. We have identified a previously unknown direct interaction between the androgen receptor and the translation initiation complex inhibitor 4EBP1 which plays a critical role in protein synthesis rates, mRNA specific translation, and disease progression in vivo. This is mediated through the hyperactivation of the downstream eIF4F translation initiation complex which usurps a network of pro-proliferation mRNAs. Importantly, using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program leading to tumor regression. As such, we have identified a new therapeutic paradigm for targeting lethal androgen receptor low prostate cancer. RNA-seq of prostrate tissue from either intact or castrated PB-Cre4;PTENLoxP/LoxP mice.