The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma

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 pat ients 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. BothHSP90AB1 andCDK9 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.
Source: Experimental Hematology and Oncology - Category: Cancer & Oncology Source Type: research