TY - JOUR
T1 - The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma
AU - Yan, Fangfang
AU - Jiang, Vivian
AU - Jordan, Alexa
AU - Che, Yuxuan
AU - Liu, Yang
AU - Cai, Qingsong
AU - Xue, Yu
AU - Li, Yijing
AU - McIntosh, Joseph
AU - Chen, Zhihong
AU - Vargas, Jovanny
AU - Nie, Lei
AU - Yao, Yixin
AU - Lee, Heng Huan
AU - Wang, Wei
AU - Bigcal, John Nelson R.
AU - Badillo, Maria
AU - Meena, Jitendra
AU - Flowers, Christopher
AU - Zhou, Jia
AU - Zhao, Zhongming
AU - Simon, Lukas M.
AU - Wang, Michael
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - CAR-T therapy
KW - Mantle cell lymphoma
KW - Resistance
KW - Single-cell RNA sequencing
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U2 - 10.1186/s40164-024-00484-9
DO - 10.1186/s40164-024-00484-9
M3 - Article
C2 - 38326887
AN - SCOPUS:85185142208
SN - 2162-3619
VL - 13
JO - Experimental Hematology and Oncology
JF - Experimental Hematology and Oncology
IS - 1
M1 - 14
ER -