MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Multiple myeloma (MM) is an incurable blood cancer where MYC alterations drive malignancy.
• MYC is a challenging therapeutic target due to its lack of druggability.
• Understanding MYC's dependencies is crucial for developing novel MM treatments.

Purpose of the Study:

• To identify genes and pathways essential for MYC-overexpressing multiple myeloma cells.
• To investigate the role of glutaminase (GLS1) and NAMPT in MYC-driven MM.
• To evaluate combination therapy targeting glutaminolysis and NAD synthesis.

Main Methods:

• Large-scale loss-of-function screens and small molecule screens were employed.
• Analysis of isogenic models, CCLE, and patient datasets identified gene dependencies.
• Functional studies delineated glutamine metabolism in MYC-overexpressing cells.
• Pharmaceutical inhibition of GLS1 and NAMPT was assessed.

Main Results:

• Glutaminase (GLS1) dependency was identified in MYC-overexpressing MM cells.
• GLS1 was found essential for the viability and proliferation of these cells.
• Pharmaceutical inhibition of NAMPT selectively impacted MYC-upregulated cells.
• Combined GLS1 and NAMPT inhibition demonstrated effectiveness in targeting MYC-driven MM.

Conclusions:

• Targeting glutaminolysis via GLS1 is a potential strategy for MYC-driven MM.
• Inhibition of NAD synthesis by NAMPT also affects MYC-driven MM cells.
• Combining GLS1 and NAMPT inhibitors offers a promising therapeutic approach for MYC-driven multiple myeloma.