NXP800激活未折叠蛋白反应，改变雄激素受体和E2F功能，从而影响去势抵抗性前列腺癌的生长。
NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth.
作者信息
Welti Jonathan, Bogdan Denisa, Figueiredo Ines, Coleman Ilsa, Jiménez Vacas Juan, Liodaki Kate, Weigl Franziska, Buroni Lorenzo, Zeng Wanting, Bernett Ilona, Bertan Claudia, Roumeliotis Theodoros I, Bhamra Amandeep, Rekowski Jan, Gurel Bora, Neeb Antje J, Ning Jian, Li Dapei, Gil Veronica S, Riisnaes Ruth, Miranda Susana, Crespo Mateus, Ferreira Ana, Tunariu Nina, Pasqua Elisa, Chessum Nicola, Cheeseman Matthew, Te Poele Robert, Powers Marissa, Carreira Suzanne, Choudhary Jyoti, Clarke Paul, Banerji Udai, Swain Amanda, Jones Keith, Yuan Wei, Workman Paul, Nelson Peter S, de Bono Johann S, Sharp Adam
机构信息
The Institute of Cancer Research, London, United Kingdom.
Fred Hutchinson Cancer Center, Seattle, Washington.
出版信息
Clin Cancer Res. 2025 Mar 17;31(6):1109-1126. doi: 10.1158/1078-0432.CCR-24-2386.
PURPOSE
Advanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced prostate cancer, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins (HSP) critical to AR functional activity.
EXPERIMENTAL DESIGN
We first did transcriptome analysis on multiple castration-resistant prostate cancer (CRPC) cohorts to correlate the association between the Gene Ontology cellular response to heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely, NXP800 (formerly CCT361814), in models of treatment-resistant prostate cancer. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in vivo model of CRPC.
RESULTS
We report that in multiple CRPC transcriptome cohorts, the Gene Ontology cellular response to heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models.
CONCLUSIONS
Overall, NXP800 has antitumor activity against treatment-resistant prostate cancer models, including molecular subtypes with limited treatment options, supporting its consideration for prostate cancer-specific clinical development.
目的
晚期前列腺癌终究是致命的，雄激素受体（AR）是主要的治疗靶点。AR信号抑制剂改善了晚期前列腺癌男性患者的总生存期，但治疗耐药不可避免，包括AR信号的重新激活。针对这些机制以阻断肿瘤生长的新型治疗方法是亟待满足的临床需求。一种有吸引力的策略是靶向对AR功能活性至关重要的热休克蛋白（HSP）。
实验设计
我们首先对多个去势抵抗性前列腺癌（CRPC）队列进行转录组分析，以关联基因本体细胞对热基因表达特征的反应与总生存期之间的关联。接下来，我们在治疗耐药性前列腺癌模型中分析了靶向热休克因子1（HSF1）途径的影响，使用一种处于临床开发阶段的抑制剂，即NXP800（原CCT361814）。最后，我们使用NXP800耐药模型和CRPC体内模型证实了我们的机制和表型研究结果。
结果
我们报告在多个CRPC转录组队列中，基因本体细胞对热基因表达特征的反应与AR信号及更差的临床结果相关。我们证明了在前列腺癌中，使用处于临床开发阶段的抑制剂NXP800靶向对细胞应激至关重要的HSF1途径的效果。用抑制剂NXP800靶向HSF1途径可降低HSP72表达，激活未折叠蛋白反应，并抑制AR和E2F介导的活性，从而抑制治疗耐药性前列腺癌模型的生长。
结论
总体而言，NXP800对治疗耐药性前列腺癌模型具有抗肿瘤活性，包括治疗选择有限的分子亚型，支持将其纳入前列腺癌特异性临床开发的考虑范围。
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