Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related death in the US. Androgen receptor (AR) signaling is the driver of both PCa development and progression and, thus, the major target of current in-use therapies. However, despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting, resistance mechanisms inevitably occur. Thus, novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival. Among the key cellular processes that are regulated by androgens, metabolic reprogramming stands out because of its intricate links with cancer cell biology. In this review, we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy. We describe the interplay between genetic alterations, metabolic vulnerabilities and castration resistance. Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression, we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies. We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression. We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies. Finally, we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers, and non-invasive approaches to monitor therapy response.

Keywords: Metabolic reprogramming; castration resistance; endocrine therapies; metabolic imaging; metabolomics; prostate cancer; therapy respo nse.

Figure 1

Metabolic alterations during PCa progression. Diagramatic representation of putative metabolic changes during progression from non-neoplastic disease to mCRPC. In normal prostate epithelial cells, the tricarboxylic acid cycle (TCA) cycle is truncated, and low rate of oxidative phosphorylation (OXPHOS) are observed. High levels of citrate are released in the seminal liquid. During malignant transformation, which is induced by genetic alterations (i.e., Pten loss, p53 loss, MYC overexpression), PCa cells reactivate the TCA cycle to oxidize citrate for energy production and convert citrate to acetyl-CoA for de-novo lipid synthesis. Fatty acids (FAs) from diet or obesity-associated adipocyte lipolysis also feed into the TCA cycle for energy production. Metabolic crosstalk is observed between cancer-associated fibroblasts (CAFs) and PCa cells, whereby CAFs provide lactate as fuel source. Increased aerobic glycolysis or the Warburg effect is observed in the metastatic stages of the disease. The Warburg effect seems to be stimulated by adipocytes in the bone marrow (BM). BM adipocytes promote the expression of glycolytic enzymes in mCRPC cells. Increased lactate secretion in TME is associated with tumor aggressiveness and metastases formation. Both de-novo lipogenesis and FAO are observed in the metastatic niche to fulfill the energetic and anabolic needs of mCRPC cells. EMT: epithelial-mesenchymal transition; TME: tumor microenvironment; PCa: prostate cancer; mCRPC: metastatic, castration-resistant prostate cancer

Figure 2

Metabolic mechanisms of resistance to endocrine therapies: the androgen receptor (AR) and lipid metabolism crosstalk. A: overview of lipid metabolism changes mediating resistance to androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI); B: schematic representation of AR signaling and lipid metabolism crosstalk. Drug targeting fatty acid (FA) synthesis and FA oxidation (FAO) are indicated as potential non-canonical approaches to inhibit AR signaling in mCRPC. CPT1: carnitine palmitoyltransferase 1; FASN: fatty acid synthase; SREBPs: sterol regulatory-element binding proteins

Figure 3

Metabolomics and metabolic imaging applications in PCa. Schematic overview of metabolomics and metabolic imaging applications in biomarker discovery and in therapy response assessment. ADT: androgen deprivation therapy; ARSI: androgen receptor signaling inhibitors; MSI: mass spectrometry imaging; MRI: magnetic resonance imaging; MRSI: magnetic resonance spectroscopy imaging; PET: positron emission tomography