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在地幔细胞淋巴瘤中对PRMT5向治疗的耐药性

Mackenzie Elizabeth Long^1,2, Shirsha Koirala¹, Shelby Sloan^1,2

¹Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH.

|October 2, 2023

概括

对PRMT5抑制剂耐药的地幔细胞淋巴瘤患者可以通过向mTOR信号来治疗. 在临床前模型中,将PRMT5抑制与mTORC1阻断相结合克服了耐药性并改善了生存率.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

薄膜细胞淋巴瘤 (MCL) 是一种具有侵略性的B细胞非霍奇金淋巴瘤,在复发时预后不佳.
蛋白质氨酸甲基转移酶5 (PRMT5) 在MCL中过度表达,对B细胞转化至关重要.
PRMT5抑制剂显示出抗瘤活性,但药物耐药性是一个重大的临床挑战.

研究的目的:

调查MCL中PRMT5抑制剂耐药性的机制.
确定克服PRMT5抑制剂耐药性的治疗策略.

主要方法:

使用患者衍生异种移植 (PDX) 和MCL的细胞系模型.
评估了对PRMT5抑制剂 (PRT-382,PRT-808) 的敏感性,并开发了耐药模型.
进行了批量和单细胞RNA测序,以确定耐药性途径.
研究使用mtORC1抑制剂 (temsirolimus) 的联合治疗.

主要成果:

在MCL模型中观察到PRMT5抑制剂耐药性,与生存率下降有关.
确定了拉巴胺素 (mTOR) 信号传输的机械标的升级作为一种关键的抗性机制.
用temsirolimus对mTORC1的向阻断克服了PRMT5抑制剂的耐药性.
组合疗法在耐药模型中显示出治疗协同作用和改善生存率.

结论:

mTOR信号激活是一个关键的途径,在MCL中调解对PRMT5抑制剂的抵抗.
联合抑制PRMT5和mTORC1代表了对抗性MCL的有前途的治疗策略.

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