Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A. In contrast to a rapid onset of cyst formation and kidney failure in mice with defective ciliogenesis, both kidney function, cyst formation discerned by magnetic resonance imaging and overall survival were strikingly improved in mice additionally lacking Raptor. However, these mice eventually succumbed to cystic kidney disease despite mTORC1 inactivation. In-depth transcriptome analysis revealed the rapid activation of other growth-promoting signaling pathways, overriding the effects of mTORC1 deletion and identified cyclin-dependent kinase (CDK) 4 as an alternate driver of cyst growth. Additional inhibition of CDK4-dependent signaling by the CDK4/6 inhibitor Palbociclib markedly slowed disease progression in mice and human organoid models of polycystic kidney disease and potentiated the effects of mTORC1 deletion/inhibition. Our findings indicate that cystic kidneys rapidly adopt bypass mechanisms typically observed in drug resistant cancers. Thus, future clinical trials need to consider combinatorial or sequential therapies to improve therapeutic efficacy in patients with cystic kidney disease.

中文翻译：

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细胞周期蛋白依赖性激酶 4 在没有 mTORC1 信号转导活性的情况下驱动囊性肾病


囊性肾病的进展与 mTORC1 信号通路的激活有关。然而，尽管临床前数据令人鼓舞，但 mTORC1 抑制剂治疗多囊肾病患者的效用仍然存在争议。为了确定 mTORC1 对囊肿发育的细胞内在作用，由于驱动蛋白家族成员基因 Kif3A 同时缺失，mTORC1 亚基基因 Raptor 在缺乏纤毛的肾小管细胞中被选择性灭活。与纤毛发生缺陷的小鼠囊肿形成和肾功能衰竭的快速发作相比，肾功能、磁共振成像识别的囊肿形成和总生存期在另外缺乏 Raptor 的小鼠中都得到了显着改善。然而，尽管 mTORC1 失活，这些小鼠最终还是死于囊性肾病。深入的转录组分析揭示了其他促进生长的信号通路的快速激活，覆盖了 mTORC1 缺失的影响，并确定了细胞周期蛋白依赖性激酶 （CDK） 4 是囊肿生长的替代驱动因素。CDK4/6 抑制剂 Palbociclib 对 CDK4 依赖性信号的额外抑制显着减缓了小鼠和多囊肾病人类类器官模型的疾病进展，并增强了 mTORC1 缺失/抑制的作用。我们的研究结果表明，囊性肾迅速采用通常在耐药癌症中观察到的旁路机制。因此，未来的临床试验需要考虑联合或序贯疗法，以提高囊性肾病患者的治疗效果。