Abstract B037: Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases

Abstract

Abstract Prostate cancer (PCa) patients’ 5-year survival is only ~30% when metastases develop. Most PCa metastases happen in bone. We seek to identify gene signatures unique for bone-metastatic PCa cells and explore potential drug candidates to specifically target PCa bone metastases (bone met). Using public RNA-Seq datasets, we defined differentially expressed genes (DE) intrinsic to PCa bone met by analyzing the DE between bone mets (MET500) and primary tumors (TCGA) and filtering out the genes shown as the DE between normal bone marrow and prostate (GTex). Similarly, we got DE intrinsic to liver met. These two intrinsic DE were further compared and functional annotation for bone met only DE was performed. We found that the bone met only up-regulated DE were significantly enriched for mitochondrial OXPHOS and electron transport chain (ETC). In contrast, no mitochondria-related terms were enriched in PCa liver met, PCa lymph node met or breast cancer bone met, suggesting unique elevated mitochondrial activities in PCa bone met. We further performed RNA-Seq analyses and determined the DE unique in intratibial xenografts (mimicking bone mets), compared to C4-2B PCa primary tumors, i.e., orthotopic or subcutaneous xenografts. OXPHOS was also positively enriched in the intratibial DE, suggesting that pre-clinical animal models recapitulate functional signatures of PCa patients and can be used for drug testing. Therefore, we hypothesized that inhibiting mitochondrial OXPHOS or ETC complex blocks PCa bone metastases. Excitingly, we found that mitochondrial ETC complex I inhibitor, IACS-010759, showed high potency and specificity in suppressing PCa cell growth without affecting osteoblasts in vitro, and significantly inhibited metastatic development of PCa cells in vivo. In summary, elevated mitochondrial activity appears to be a unique signature and phenotype for PCa bone met and mitochondria-interrupting drugs selectively suppress the growth of PCa cells without affecting normal cells in the bone microenvironment such as osteoblasts. Blocking mitochondria hyperactivation is a potential approach against PCa bone met. Citation Format: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li. Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B037.