KETONE BODY METABOLISM PROMOTES PROSTATE CANCER CASTRATE RESISTANT PROGRESSION.

PABLO SANCHIS; JUN YANG; VALERIA ANTICO ARCIUCH; ANH HOANG; MARK TITUS; JOHN ARAUJO; NORA NAVONE; ESTEFANIA LABANCA; PETER D A SHEPHERD; NICOLAS ANSELMINO; XIMING TANG; ELENI EFSTATHIOU; CHRISTOPHER LOGOTHETIS; GERALDINE GUERON; JUAN BIZZOTTO; ALEJANDRA PAEZ; SOFIA LAGE VICKERS; MARIA GABRIELA RASO; JAVIER COTIGNOLA; ELBA VAZQUEZ

Virtual

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica 2021; 2021

SAIC

The mechanisms underlying prostate cancer (PCa) castration resistance (CRPC) after androgen deprivation therapy (ADT) include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. Several studies have discussed the fact that a dietary restriction, such as in ketogenic diets (KD), impairs tumor growth rate, however, the intricacy of metabolic pathways associated with PCa progression remains elusive. Here, using PCa patient-derived xenografts (PDXs) mimicking the response of the human donor to ADT, we performed a comprehensive metabolomic analysis of PCa PDXs that relapsed following castration. We discovered a metabolic shift from high glycolytic activity to exacerbated ketone body (KB) metabolism. These results indicated that a subpopulation of CRPCs that progresses with partial or complete loss of AR dependence are fueled by KB. We confirmed (IHC) that the expression of critical ketolytic enzymes (ACAT1, OXCT1, BDH) was significantly augmented after castration-resistant progression in both the PDX tumor and its human donor tissue (P