Therapeutic Target Discovery for Multiple Myeloma: Identifying Druggable Genes via Mendelian Randomization.

Area of Science:

• Genetics
• Oncology
• Pharmacology

Background:

• Multiple myeloma (MM) is a bone marrow malignancy with significant challenges in relapse and drug resistance.
• Novel therapeutic targets are crucial for improving MM treatment outcomes.

Purpose of the Study:

• To identify novel druggable genes for multiple myeloma (MM) using Mendelian randomization (MR).
• To validate potential therapeutic agents targeting identified genes for MM treatment.

Main Methods:

• Mendelian randomization (MR) analysis to identify causal genes.
• Transcriptome-wide association study (TWAS) and colocalization analysis for validation.
• MR-PheWAS for off-target effects, molecular docking, and functional assays for drug efficacy.

Main Results:

• Nine druggable genes were identified via MR, with ORM1 and OVGP1 showing strong evidence from TWAS and colocalization.
• ORM1 and OVGP1 were significantly downregulated in MM cells.
• Pregnenolone (ORM1 agonist) and irinotecan (OVGP1 agonist) inhibited MM cell viability and upregulated gene expression.

Conclusions:

• ORM1 and OVGP1 represent novel therapeutic targets for multiple myeloma.
• Pregnenolone and irinotecan demonstrate potential for clinical application in MM treatment.
• Findings offer insights into MM pathogenesis and strategies to overcome drug resistance.