Metabolic and imaging phenotypes associated withRB1loss in castrate resistant prostate cancer

Abstract

AbstractAdvanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but the majority of patients eventually develop resistance and progress to castration resistant prostate cancer (CRPC). Loss ofRB1in CRPC tumors is correlated with rapid progression and poor patient survival, and in combination withTP53loss, predisposes to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressing CRPC is clinically associated with higher [18F]DG-PET SUVmaxvalues, it is unknown whether inactivation ofRB1and/orTP53is a driver of increased glucose import. To study this, we used a cohort of PDX-derived CRPC organoids and observed that [18F]DG uptake is higher in AR positive adenocarcinoma (ARPC) compared with NEPC and was not associated with genotype, includingRB1status. In two ARPC models, experimental loss of RB1 increased glycolysis and oxygen consumption. While these metabolic changes were not detected in vitro or in vivo by [18F]DG-PET,13C-hyperpolarized magnetic resonance spectroscopy showed significant differences in lactate dehydrogenase flux upon loss ofRB1. Loss of TP53 and RB1 created a new phenotype where glucose was diverted to the pentose phosphate pathway and into glycogen synthesis. These data demonstrate an increased glycolytic phenotype associated withRB1loss in ARPC unlinked to glucose uptake and suggest that the tumor microenvironment may play a major role in determining levels of [18F]DG uptake in vivo.