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.

在我们以前的研究中，我们观察到雄激素剥夺疗法（ADT）可能会诱导MAPK或JNK信号传导的代偿性增加。在这里，我们测试了MEK抑制剂PD0325901和GSK1120212，ERK1 / 2抑制剂GDC-0994和JNK抑制剂AS602801单独以及与AR抑制剂enzalutamide（ENZ）联合使用对雄激素敏感的LNCaP细胞和抗雄激素的C4的作用-2和22Rv1细胞。恩扎鲁胺与AS602801联合可协同杀死LNCaP，C4-2和22Rv1细胞，并减少LNCaP和C4-2细胞的迁移和侵袭。我们在体内研究了enzalutamide与AS602801的组合使用荧光素酶标记的LNCaP异种移植物，并观察到ENZ与AS602801的组合与单独使用任一药物相比均能显着抑制肿瘤的生长。重要的是，联合治疗导致AR mRNA和蛋白质的大量损失。出人意料的是，机理研究和纳米串数据表明，AS602801可能激活JNK信号传导来诱导细胞凋亡。由于AS602801具有足够的安全性和毒性特征，可以在临床试验中从I期发展到II期，因此重新使用该化合物可能为CRPC患者的临床治疗提供了快速翻译的机会。