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Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer
Paolo Chetta1,2, Giorgia Zadra3,4
1University of Milan, Milan 20122, Italy.
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.
Insights
Prostate cancer (PCa) progression is driven by androgen receptor (AR) signaling. Understanding how AR signaling impacts cancer metabolism and lipid metabolism is key to overcoming resistance to endocrine therapies and improving patient survival.
Area of Science:
- Oncology
- Cancer Metabolism
- Endocrine Therapy Resistance
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in the US.
- Androgen receptor (AR) signaling drives PCa development and progression, making it a primary therapeutic target.
- Resistance to AR-signaling inhibitors is a major clinical challenge, necessitating novel treatment strategies.
Purpose of the Study:
- To review how androgens regulate cancer and lipid metabolism in PCa.
- To explore the link between metabolic reprogramming and resistance to endocrine therapy.
- To discuss potential therapeutic strategies targeting metabolic vulnerabilities.
Main Methods:
- Literature review focusing on androgen regulation of metabolism in PCa.
- Analysis of the interplay between genetic alterations, metabolic vulnerabilities, and castration resistance.
- Examination of the association between diet, obesity, and anti-androgen therapy resistance.
Main Results:
- Androgen signaling intricately regulates cancer cell metabolism, particularly lipid metabolism, contributing to endocrine therapy resistance.
- Genetic alterations and metabolic reprogramming are linked to castration resistance in PCa.
- Diet and obesity are associated with resistance to anti-androgen therapies.
- Metabolic symbiosis between PCa cells and the tumor microenvironment may drive progression.
Conclusions:
- Targeting PCa metabolic vulnerabilities offers a potential synthetic lethality approach to enhance endocrine therapies.
- Advances in analytical technologies and metabolic imaging are identifying new biomarkers for prognosis and therapy monitoring.
- Developing strategies to overcome metabolic reprogramming is crucial for improving PCa patient outcomes.
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