The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma.
Fangfang YanVivian JiangAlexa JordanYuxuan CheYang LiuQingsong CaiYu XueYijing LiJoseph McIntoshZhihong ChenJovanny VargasLei NieYixin YaoHeng-Huan LeeWei WangJohnNelson R BigcalMaria BadilloJitendra MeenaChristopher FlowersJia ZhouZhongming ZhaoLukas M SimonMichael WangPublished in: Experimental hematology & oncology (2024)
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.
Keyphrases
- heat shock protein
- single cell
- cell cycle
- heat shock
- transcription factor
- heat stress
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- ejection fraction
- type diabetes
- adipose tissue
- cancer therapy
- metabolic syndrome
- long non coding rna
- insulin resistance
- single molecule
- bone marrow
- prognostic factors
- peritoneal dialysis
- binding protein
- drug delivery
- replacement therapy
- glycemic control
- cell cycle arrest