LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy.

IF 12.5 1区 医学 Q1 ONCOLOGY
Shu Ning, Cameron M Armstrong, Enming Xing, Amy R Leslie, Richard Y Gao, Masuda Sharifi, Zachary A Schaaf, Wei Lou, Xiangrui Han, Desiree H Xu, Rui Yang, Jeffrey Cheng, Shabber Mohammed, Nicholas Mitsiades, Chengfei Liu, Alan P Lombard, Chun-Yi Wu, Xiaolin Cheng, Pui-Kai Li, Allen C Gao
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Abstract

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer. Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer.

LX1 靶向雄激素受体变异体和 AKR1C3,克服晚期前列腺癌的耐药性。
对雄激素受体(AR)靶向疗法等当前标准治疗方法产生耐药性仍然是晚期前列腺癌治疗中的一大挑战。目前迫切需要针对主要耐药性驱动因素(如 AR-V7 等 AR 变异体和 AKR1C3 等类固醇生成酶)的治疗策略,以改善晚期前列腺癌患者的预后。在这里,我们设计、合成并表征了一类靶向 AR/AR 变体和 AKR1C3 的 LX 化合物。分子对接表明,LX化合物与AKR1C3活性位点结合。LX1 阻断了 AKR1C3 的酶活性,抑制了雄烯二酮向睾酮的转化。LX 化合物还降低了 AR/AR-V7 的表达,并下调了其靶基因。在体外,LX1 可抑制对恩扎鲁胺、阿比特龙、阿帕鲁胺和达罗鲁胺等抗雄激素产生耐药性的前列腺癌细胞的生长。在体内使用 LX1 能显著减少肿瘤生长、降低血清 PSA 水平和瘤内睾酮水平,而不影响小鼠体重。此外,LX1还能克服恩杂鲁胺治疗的耐药性,而LX1与恩杂鲁胺联合使用能进一步抑制肿瘤生长。总之,LX1在降低瘤内睾酮和AR信号传导方面的双重作用,以及它与标准疗法在耐药模型中的协同作用,凸显了它作为一种有价值的晚期前列腺癌治疗选择的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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