Proteomics

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BCL-2 Regulation and Upstream Signal Transduction Modulate Venetoclax Resistance in Multiple Myeloma: New Avenues for Therapeutic Intervention

ABSTRACT: This study aimed to investigate the mechanisms underlying venetoclax (VTX) resistance in multiple myeloma (MM) and develop strategies to prevent or overcome resistance. VTX resistant human myeloma cell lines (HMCLs) were established and analyzed using whole exome sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays, along with samples from MM patients collected before and after VTX administration. Acquired VTX-resistance in MM was largely associated with BCL-2 family regulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2 and downregulation of pro-apoptotic members. No BCL-2 mutation was detected in resistant cell lines or relapse patient samples. We also identified upstream signaling pathways involved in BCL-2 family regulation during acquired resistance, such as cytokine, growth factor receptor tyrosine kinase (RTK)-activated signaling, including the PI3K pathway. MCL-1 stability was also investigated through modulation of post-translational modification, but targeting MCL-1 stability via specific inhibitors had limited success in enhancing VTX sensitivity. Co-inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Additionally, the inhibition of AURKA and mitochondrial respiration also affected VTX sensitivity in some resistant HMCLs. The findings underscore the importance of personalized approaches to overcome resistance in relapsed patients, suggesting that combining venetoclax with MCL-1 and BCL-XL inhibitors, or targeting upstream regulatory pathways, warrants further investigation to improve patient outcomes and prolong survival in MM.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Akhilesh Pandey  

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD047149 | Pride | 2025-05-06

REPOSITORIES: Pride

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Eclipse_2023Feb3_VTX_MM_TMT8plex_TP_24F_final.pdResult Other
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Publications

Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic protein  ...[more]

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