Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive-variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone. Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.

Molecular cancer research : MCR. 2022 Sep 16 [Epub ahead of print]

Federica Mossa, Daniele Robesti, Ramachandran Sumankalai, Eva Corey, Mark Titus, Yuqi Kang, Jianhua Zhang, Alberto Briganti, Francesco Montorsi, Christopher P Vellano, Joseph R Marszalek, Daniel E Frigo, Christopher J Logothetis, Taranjit S Gujral, Eleonora Dondossola

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Vita Salute San Raffaele University, Milan, Italy, Milan, Italy., The University of Texas MD Anderson Cancer Center, United States., University of Washington, SEATTLE, WA, United States., University of California, San Diego, La Jolla, CA, United States., The University of Texas MD Anderson Cancer Center, Houston., University Vita-Salute San Raffaele, Milan, Italy., Department of Urology, Vita Salute San Raffaele University, Milan, Italy, Italy., The University of Texas MD Anderson Cancer Center, Houston, TX, United States., The University of Texas MD Anderson Cancer Center, Houston, United States., Fred Hutchinson Cancer Center, Seattle, WA, United States.

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