CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
HSP90-MYC-CDK9 网络驱动套细胞淋巴瘤的治疗耐药
英文原题：The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma.
查看英文原题
The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma.
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中文摘要
Brexucabtagene autoleucel CAR-T 疗法在套细胞淋巴瘤中高效克服对 Bruton 酪氨酸激酶抑制剂（BTKi）的耐药性。
然而，许多患者在 CAR-T 治疗后复发，结局不良。为剖析对 BTKi 和 CAR-T 疗法序贯耐药的潜在机制，我们对 25 例接受 BTKi 和/或 CAR-T 治疗患者的 66 份样本进行了单细胞 RNA 测序分析，并开展了深入的生物信息学分析。
我们的分析显示，MYC 活性随序贯耐药而逐渐升高。HSP90AB1（热休克蛋白90α家族B类成员1），一个 MYC 靶点，被确定为 CAR-T 耐药的早期驱动因子。CDK9（细胞周期蛋白依赖性激酶9），另一个 MYC 靶点，在 Dual-R 样本中显著上调。HSP90AB1 和 CDK9 的表达均与 MYC 活性水平相关。药物联合靶向 HSP90 和 CDK9 协同降低 MYC 活性，导致强效抗 MCL 活性。
总之，我们的研究揭示 HSP90-MYC-CDK9 网络是治疗耐药的主要驱动力。
展开英文摘要原文
Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma.
However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics analysis.
Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 (Cyclin-dependent kinase 9), another MYC target, was significantly upregulated in Dual-R samples.
Both HSP90AB1 and CDK9 expression were correlated with MYC activity levels. Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.
论文信息
- 作者
- Yan F、Jiang V、Jordan A、Che Y、Liu Y、Cai Q、Xue Y、Li Y
- 第一作者单位
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.United States
- 通讯作者单位
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. miwang@mdanderson.org.United States
- 期刊
- Experimental hematology & oncology2024 Feb 7
- 原文标识
- PubMed 38326887 · DOI 10.1186/s40164-024-00484-9
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