학술논문
The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma
Document Type
article
Author
Fangfang Yan; Vivian Jiang; Alexa Jordan; Yuxuan Che; Yang Liu; Qingsong Cai; Yu Xue; Yijing Li; Joseph McIntosh; Zhihong Chen; Jovanny Vargas; Lei Nie; Yixin Yao; Heng-Huan Lee; Wei Wang; JohnNelson R. Bigcal; Maria Badillo; Jitendra Meena; Christopher Flowers; Jia Zhou; Zhongming Zhao; Lukas M. Simon; Michael Wang
Source
Experimental Hematology & Oncology, Vol 13, Iss 1, Pp 1-19 (2024)
Subject
Language
English
ISSN
2162-3619
Abstract
Abstract 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.