Investigating the potential molecular players and therapeutic drug molecules in carfilzomib resistant multiple...

Area of Science:

• Hematological Malignancies
• Cancer Genomics
• Drug Resistance Mechanisms

Background:

• Multiple myeloma (MM) is a common hematological malignancy with limited cure options due to acquired drug resistance.
• Carfilzomib (Cfz) is a key therapy for MM, but resistance limits its efficacy.
• The mechanisms underlying Cfz resistance in MM are poorly understood.

Purpose of the Study:

• To investigate differentially expressed genes (DEGs), microRNAs (miRNAs), and transcription factors (TFs) in Cfz-resistant versus Cfz-sensitive MM cell lines.
• To identify molecular pathways and potential therapeutic targets involved in Cfz resistance.
• To gain new insights into the mechanisms of acquired Cfz resistance in MM.

Main Methods:

• Analysis of microarray datasets from the Gene Expression Omnibus (GEO) database using GEO2R.
• Identification of common DEGs via Venn diagrams.
• Gene Ontology (GO) and pathway enrichment analysis using DAVID.
• Construction of protein-protein interaction (PPI) networks using STRING and Cytoscape.
• Investigation of genetic alterations using the COSMIC database.
• Analysis of DEG-miRNA and DEG-TF interactions using mirDIP, TRRUST, and miRNet.
• Drug-gene interaction analysis using DGIdb.

Main Results:

• Several common DEGs were identified in Cfz-resistant MM.
• PDGF, VEGF, and Wnt signaling pathways were significantly enriched, suggesting their role in MM progression.
• hsa-mir-124-3p and hsa-mir-26a-5p were identified as potential targeting miRNAs for DEGs.
• Potential therapeutic molecules, including dabrafenib, vemurafenib, and venetoclax, were identified.

Conclusions:

• The study identified key molecular players and pathways contributing to carfilzomib resistance in multiple myeloma.
• Specific miRNAs and signaling pathways (PDGF, VEGF, Wnt) are implicated in MM progression and drug resistance.
• Identified drug molecules offer potential therapeutic strategies to overcome Cfz resistance in MM.