HSP90-MYC-CDK9网络驱动了上衣细胞淋巴瘤的治疗耐药性
Fangfang Yan1,2, Vivian Jiang3, Alexa Jordan2
1Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
Experimental hematology & oncology
|February 7, 2024
概括
在上衣细胞淋巴瘤中对布鲁顿的氨酸激酶抑制剂 (BTKi) 和CAR-T疗法的序列性耐药性是由HSP90-MYC-CDK9网络驱动的. 针对这种途径提供了一个有希望的战略,以克服治疗耐药性.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 分子生物学分子生物学
背景情况:
- 布雷克苏卡巴泰基因自细胞CAR-T疗法显示对布鲁顿的抗氨酸激酶抑制剂 (BTKi) 抗性地幔细胞淋巴瘤 (MCL) 的疗效.
- 治疗耐药性和CAR-T治疗后复发仍然是重大挑战,导致患者的治疗结果不佳.
研究的目的:
- 调查覆盖细胞淋巴瘤中对BTKi和CAR-T疗法的序列性耐药性背后的分子机制.
- 确定关键的分子驱动因素和潜在的治疗目标,以克服治疗耐药性.
主要方法:
- 在接受BTKi和/或CAR-T治疗的25名患者的66个样本上进行了单细胞RNA测序.
- 进行了深入的生物信息学分析,以确定与耐药性相关的差异表达基因和途径.
主要成果:
- 观察到MYC活动的逐渐增加,随着对治疗的顺序性耐药性.
- HSP90AB1 (热冲击蛋白90α家族B类成员1) 被确定为CAR-T耐药性的早期驱动因素.
- 在双抗性样本中,CDK9 (循环素依赖性激酶9) 被上调,HSP90AB1和CDK9的表达与MYC活性相关.
结论:
- HSP90-MYC-CDK9信号网络是地幔细胞淋巴瘤连续治疗耐药性的主要驱动因素.
- 在临床前模型中,HSP90和CDK9的药物共同向协同降低了MYC活性,并显示出强大的抗MCL活性.
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