Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer.
Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer.
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DOI：
10.3390/cancers15215273
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发表时间：
2023-11-03
期刊：
影响因子：
5.2
通讯作者：
Gao, Allen C.
中科院分区：
文献类型：
--
作者：
Schaaf, Zachary A.;Ning, Shu;Leslie, Amy R.;Sharifi, Masuda;Han, Xianrui;Armstrong, Cameron;Lou, Wei;Lombard, Alan P.;Liu, Chengfei;Gao, Allen C.
抗去势前列腺癌(CRPC)的治疗方法包括下一代抗雄激素疗法(NGATS)、紫杉烷疗法和PARP抑制剂(PARPI)。然而，耐药性经常发生在治疗类别之间和治疗类别内，这可能会使顺序治疗选择复杂化。我们开发了获得性耐药模型来研究治疗耐药。我们的发现表明，尽管Ngat耐药细胞对其他NGAT具有交叉耐药性，但它们对紫杉烷和奥拉帕利布仍然敏感。对多西紫杉醇耐药的细胞对卡巴紫杉醇和奥拉帕利表现出交叉耐药，但对NGATS有反应。奥拉帕利耐药细胞对其他PARPI交叉耐药，但对NGATS和多西紫杉醇仍敏感。我们的研究强调了合理的药物测序在CRPC治疗和耐药的潜在机制中的重要性。目前对去势耐受前列腺癌(CRPC)的常见治疗方法通常属于三大类之一：包括苯扎鲁胺、醋酸阿比特龙、阿帕鲁胺和达鲁他胺的下一代抗雄激素疗法(NGAT)；以多西紫杉醇为代表的紫杉烷疗法；以及以奥拉帕利为代表的PARP抑制剂(PARPI)。尽管这些治疗显示了许多患者的疗效并改善了结果，但由于出现治疗耐药，一些患者无法存活。由于对治疗顺序如何影响CRPC中治疗交叉耐药的发展的有限了解，临床情况进一步复杂化。我们已经从C4-2B细胞中建立了多种获得性治疗耐药细胞亚系的CRPC模型。这些菌株包括C4-2B MDVR、C4-2B Abir、C4-2B Apar、C4-2B DaroR、TaxR和2B-olapR，它们分别对苯扎鲁胺、阿比特龙、阿帕鲁胺、达鲁他胺、多西紫杉醇和奥拉帕利产生抗性。这些模型有助于分析基因表达和评估对各种治疗的反应。我们的发现揭示了耐Ngat细胞亚系之间明显的交叉耐药特征。具体地说，对苯扎鲁胺的耐药性导致对阿比特龙的耐药性，反之亦然，同时保持对紫杉烷和奥拉帕利的敏感性。相反，对多西紫杉醇具有获得性耐药的细胞对卡巴紫杉醇和奥拉帕利都表现出交叉耐药，但对苯扎鲁胺和阿比特龙等NGATS保持敏感。与亲本细胞相比，Olip R细胞对奥拉帕利具有显著的耐药性，但对NGATS和多西紫杉醇仍有反应。此外，Olip R模型对其他临床相关的PARP抑制剂表现出交叉耐药性，包括rucaparib、niraparib和talazoparib。RNA测序分析揭示了一个复杂的基因表达变化网络，这些基因表达影响信号通路、能量代谢和凋亡信号，这些信号对癌症的进化和进展至关重要。这些数据表明，不同药物类别之间的耐药机制是不同的。值得注意的是，与奥拉帕利布和多西紫杉醇耐药亚系的稳定表达相比，耐Ngat的亚系表现出显著的雄激素调节基因下调。这些结果可能具有临床意义，因为这些结果表明，一类治疗可以与另一类治疗进行排序，但在对同一类药物进行排序时应谨慎。
Castration-resistant prostate cancer (CRPC) treatments include next-generation anti-androgen therapies (NGATs), taxane therapy, and PARP inhibitors (PARPi). However, resistance often occurs across and within therapeutic classes, which can complicate sequential treatment options. We developed acquired resistant models to study therapeutic resistance. Our findings indicate that while NGAT-resistant cells are cross-resistant to other NGATs, they remain sensitive to taxanes and olaparib. Cells resistant to docetaxel display cross-resistance to cabazitaxel and olaparib but respond to NGATs. Olaparib-resistant cells are cross-resistant to other PARPi but still sensitive to NGATs and docetaxel. Our research underscores the significance of rationale drug sequencing in CRPC treatment and underlying mechanisms of resistance. 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.
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影响因子：
28.2
作者：
Goodall J;Mateo J;Yuan W;Mossop H;Porta N;Miranda S;Perez-Lopez R;Dolling D;Robinson DR;Sandhu S;Fowler G;Ebbs B;Flohr P;Seed G;Rodrigues DN;Boysen G;Bertan C;Atkin M;Clarke M;Crespo M;Figueiredo I;Riisnaes R;Sumanasuriya S;Rescigno P;Zafeiriou Z;Sharp A;Tunariu N;Bianchini D;Gillman A;Lord CJ;Hall E;Chinnaiyan AM;Carreira S;de Bono JS;TOPARP-A investigators
通讯作者：
TOPARP-A investigators
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping
DOI：
10.1016/j.urolonc.2017.01.020
发表时间：
2017-05-01
影响因子：
2.7
作者：
Crawford, E. David;Petrylak, Daniel;Sartor, Oliver
通讯作者：
Sartor, Oliver
影响因子：
5.7
作者：
Lombard, Alan P.;Liu, Liangren;Gao, Allen C.
通讯作者：
Gao, Allen C.