Current common treatments for castration-resistant prostate cancer (CRPC) typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown efficacy and have improved outcomes for many patients, some do not survive due to the emergence of therapeutic resistance. The clinical landscape is further complicated by limited knowledge about how the sequence of treatments impacts the development of therapeutic cross-resistance in CRPC. We have developed multiple CRPC models of acquired therapeutic resistance cell sublines from C4-2B cells. These include C4-2B MDVR, C4-2B AbiR, C4-2B ApaR, C4-2B DaroR, TaxR, and 2B-olapR, which are resistant to enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, and olaparib, respectively. These models are instrumental for analyzing gene expression and assessing responses to various treatments. Our findings reveal distinct cross-resistance characteristics among NGAT-resistant cell sublines. Specifically, resistance to enzalutamide induces resistance to abiraterone and vice versa, while maintaining sensitivity to taxanes and olaparib. Conversely, cells with acquired resistance to docetaxel exhibit cross-resistance to both cabazitaxel and olaparib but retain sensitivity to NGATs like enzalutamide and abiraterone. OlapR cells, significantly resistant to olaparib compared to parental cells, are still responsive to NGATs and docetaxel. Moreover, OlapR models display cross-resistance to other clinically relevant PARP inhibitors, including rucaparib, niraparib, and talazoparib. RNA-sequencing analyses have revealed a complex network of altered gene expressions that influence signaling pathways, energy metabolism, and apoptotic signaling, pivotal to cancer’s evolution and progression. The data indicate that resistance mechanisms are distinct among different drug classes. Notably, NGAT-resistant sublines exhibited a significant downregulation of androgen-regulated genes, contrasting to the stable expression noted in olaparib and docetaxel-resistant sublines. These results may have clinical implications by showing that treatments of one class can be sequenced with those from another class, but caution should be taken when sequencing drugs of the same class.
目前去势抵抗性前列腺癌（CRPC）的常见治疗主要分为三大类：以恩杂鲁胺、阿比特龙、阿帕鲁胺和达洛鲁胺为代表的新一代抗雄激素疗法（NGAT）；以多西他赛为代表的紫杉烷类化疗；以及以奥拉帕尼为代表的PARP抑制剂（PARPi）。尽管这些疗法已显示出疗效并改善了许多患者的预后，但部分患者因产生治疗耐药性而未能存活。由于对治疗顺序如何影响CRPC治疗交叉耐药性发展的认识有限，临床情况变得更加复杂。我们利用C4-2B细胞建立了多种获得性治疗耐药的CRPC模型细胞亚系，包括分别对恩杂鲁胺、阿比特龙、阿帕鲁胺、达洛鲁胺、多西他赛和奥拉帕尼耐药的C4-2B MDVR、C4-2B AbiR、C4-2B ApaR、C4-2B DaroR、TaxR和2B-olapR。这些模型有助于分析基因表达并评估对各种治疗的反应。我们的研究揭示了NGAT耐药细胞亚系之间独特的交叉耐药特征：恩杂鲁胺耐药会诱导阿比特龙耐药，反之亦然，同时保持对紫杉烷类和奥拉帕尼的敏感性；相反，获得多西他赛耐药的细胞对卡巴他赛和奥拉帕尼均表现出交叉耐药性，但仍对恩杂鲁胺和阿比特龙等NGAT药物敏感；与亲本细胞相比，奥拉帕尼耐药细胞对奥拉帕尼显著耐药，但仍对NGAT药物和多西他赛有反应。此外，奥拉帕尼耐药模型对其他临床相关的PARP抑制剂（如卢卡帕利、尼拉帕利和他拉唑帕利）也表现出交叉耐药性。RNA测序分析揭示了一个复杂的基因表达改变网络，这些改变影响了信号通路、能量代谢和凋亡信号，对癌症的演变和进展至关重要。数据表明，不同药物类别的耐药机制各不相同。值得注意的是，NGAT耐药亚系中雄激素调节基因显著下调，而奥拉帕尼和多西他赛耐药亚系中这些基因表达稳定。这些结果可能具有临床意义，表明不同类别的治疗可以序贯使用，但在序贯使用同类药物时应谨慎。
Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer
肿瘤(癌症)患者之家