Author:
Yan Fangfang,Jiang Vivian,Jordan Alexa,Che Yuxuan,Liu Yang,Cai Qingsong,Xue Yu,Li Yijing,McIntosh Joseph,Chen Zhihong,Vargas Jovanny,Nie Lei,Yao Yixin,Lee Heng-Huan,Wang Wei,Bigcal JohnNelson R.,Badillo Maria,Meena Jitendra,Flowers Christopher,Zhou Jia,Zhao Zhongming,Simon Lukas M.,Wang Michael
Abstract
AbstractBrexucabtagene 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.
Funder
NIH
CPRIT
MD Anderson B-cell Lymphoma Moon Shot Project
The Gary Rogers Foundation
Kinder Foundation
Cullen Foundation
start-up research funds by MD Anderson Cancer Center
NIH-funded Cancer Center Support Grant
NIH Core Grant for the Sequencing and Microarray Facility
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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