Chetta Paolo, Zadra Giorgia
University of Milan, Milan 20122, Italy.
Current Address: Boehringer Ingelheim RCV GmbH & Co. KG, Dr.-Boehringer-Gasse 5-11, Vienna 1121, Austria.
Cancer Drug Resist. 2021 Mar 19;4(1):143-162. doi: 10.20517/cdr.2020.54. eCollection 2021.
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.
前列腺癌（PCa）是美国癌症相关死亡的第二大主要原因。雄激素受体（AR）信号传导是PCa发生和进展的驱动因素，因此也是当前正在使用的治疗方法的主要靶点。然而，尽管第二代AR信号抑制剂在转移性环境中具有生存益处，但耐药机制仍不可避免地出现。因此，需要新的策略来规避耐药性的发生，从而提高PCa患者的生存率。在受雄激素调节的关键细胞过程中，代谢重编程因其与癌细胞生物学的复杂联系而脱颖而出。在这篇综述中，我们讨论了癌症代谢，尤其是脂质代谢如何受雄激素调节，并导致对内分泌治疗产生耐药性。我们描述了基因改变、代谢脆弱性和去势抵抗之间的相互作用。由于PCa细胞会调整其代谢以适应过量的营养供应，从而促进癌症进展，我们综述了目前关于饮食/肥胖与抗雄激素治疗耐药性之间关联的知识。我们简要描述了PCa细胞与肿瘤微环境之间的代谢共生关系，以及这种相互作用如何可能促进PCa的进展。我们讨论了如何应对PCa的代谢脆弱性，这代表了一种对内分泌治疗具有合成致死性的潜在方法。最后，我们描述了分析技术和代谢成像的不断进步如何导致潜在的新预后和预测生物标志物的识别，以及监测治疗反应的非侵入性方法。
