Multi-omics investigation of the resistance mechanisms of pomalidomide in multiple myeloma

Frontiers in Oncology

Oncology

Hua Jiang¹  WeiJun Fu¹  Lu Li¹  Yuanteng Zhang²  Chenyu Li³  Wei Yu³  Yan Zhuang⁴ 

[1] Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China;Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China;State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China;State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China;Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China;

关键词: multiple myeloma;    pomalidomide;    drug resistance;    complement;    glycine;   

DOI  :  10.3389/fonc.2023.1264422

 received in 2023-07-20, accepted in 2023-08-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundDespite significant therapeutic advances over the last decade, multiple myeloma remains an incurable disease. Pomalidomide is the third Immunomodulatory drug that is commonly used to treat patients with relapsed/refractory multiple myeloma. However, approximately half of the patients exhibit resistance to pomalidomide treatment. While previous studies have identified Cereblon as a primary target of Immunomodulatory drugs’ anti-myeloma activity, it is crucial to explore additional mechanisms that are currently less understood.MethodsTo comprehensively investigate the mechanisms of drug resistance, we conducted integrated proteomic and metabonomic analyses of 12 plasma samples from multiple myeloma patients who had varying responses to pomalidomide. Differentially expressed proteins and metabolites were screened, and were further analyzed using pathway analysis and functional correlation analysis. Also, we estimated the cellular proportions based on ssGSEA algorithm. To investigate the potential role of glycine in modulating the response of MM cells to pomalidomide, cell viability and apoptosis were analyzed.ResultsOur findings revealed a consistent decrease in the levels of complement components in the pomalidomide-resistant group. Additionally, there were significant differences in the proportion of T follicular helper cell and B cells in the resistant group. Furthermore, glycine levels were significantly decreased in pomalidomide-resistant patients, and exogenous glycine administration increased the sensitivity of MM cell lines to pomalidomide.ConclusionThese results demonstrate distinct molecular changes in the plasma of resistant patients that could be used as potential biomarkers for identifying resistance mechanisms for pomalidomide in multiple myeloma and developing immune-related therapeutic strategies.

【 授权许可】

Unknown   
Copyright © 2023 Zhuang, Li, Jiang, Li, Zhang, Yu and Fu