Li Zhenghong, Sun Carrie, Tao Sijia, Osunkoya Adeboye O, Arnold Rebecca S, Petros John A, Zu Xiongbing, Moreno Carlos S
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA; Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
Department of Urology, Emory University, Atlanta, GA 30322, USA.
Transl Oncol. 2020 Apr;13(4):100751. doi: 10.1016/j.tranon.2020.100751. Epub 2020 Mar 18.
In our previous study, we observed that androgen deprivation therapy (ADT) may induce a compensatory increase in MAPK or JNK signaling. Here, we tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with the AR inhibitor enzalutamide (ENZ) in androgen-sensitive LNCaP cells and androgen-resistant C4-2 and 22Rv1 cells. Enzalutamide combined with AS602801 synergistically killed LNCaP, C4-2, and 22Rv1 cells, and decreased migration and invasion of LNCaP and C4-2 cells. We studied the combination of enzalutamide with AS602801 in vivo using luciferase labeled LNCaP xenografts, and observed that combination of ENZ with AS602801 significantly suppressed tumor growth compared with either drug alone. Importantly, combination therapy resulted in dramatic loss of AR mRNA and protein. Surprisingly, mechanistic studies and Nanostring data suggest that AS602801 likely activates JNK signaling to induce apoptosis. Since AS602801 had sufficient safety and toxicity profile to advance from Phase I to Phase II in clinical trials, repurposing of this compound may represent an opportunity for rapid translation for clinical therapy of CRPC patients.
在我们之前的研究中，我们观察到雄激素剥夺疗法（ADT）可能会诱导MAPK或JNK信号通路的代偿性增加。在此，我们测试了MEK抑制剂PD0325901和GSK1120212、ERK1/2抑制剂GDC-0994以及JNK抑制剂AS602801单独使用以及与雄激素受体（AR）抑制剂恩杂鲁胺（ENZ）联合使用时，对雄激素敏感的LNCaP细胞以及雄激素抵抗的C4-2和22Rv1细胞的影响。恩杂鲁胺与AS602801联合使用可协同杀死LNCaP、C4-2和22Rv1细胞，并降低LNCaP和C4-2细胞的迁移和侵袭能力。我们使用荧光素酶标记的LNCaP异种移植瘤在体内研究了恩杂鲁胺与AS602801的联合用药情况，观察到与单独使用任何一种药物相比，ENZ与AS602801联合使用可显著抑制肿瘤生长。重要的是，联合治疗导致AR mRNA和蛋白显著减少。令人惊讶的是，机制研究和纳米串数据表明，AS602801可能激活JNK信号通路以诱导细胞凋亡。由于AS602801具有足够的安全性和毒性特征，能够在临床试验中从I期推进到II期，因此重新利用该化合物可能为CRPC患者的临床治疗提供快速转化的机会。
