Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma

Area of Science:

• Oncology
• Cellular Metabolism
• Molecular Biology

Background:

• Venetoclax (BCL-2 antagonist) is effective in multiple myeloma (MM) with the 11;14 translocation, but the mechanism is unclear.
• Cellular energetics and metabolism differences between t(11;14) and non-t(11;14) MM are being investigated.
• Venetoclax-sensitive MM exhibits reduced mitochondrial respiration.

Purpose of the Study:

• To investigate the mechanistic basis of venetoclax efficacy in multiple myeloma.
• To explore the role of cellular energetics and mitochondrial respiration in venetoclax sensitivity.
• To identify potential biomarkers for predicting venetoclax response.

Main Methods:

• Comparative analysis of cellular energetics and metabolism in t(11;14) and non-t(11;14) MM.
• Assessment of electron transport chain (ETC) Complex I and Complex II activities.
• Inhibition of Complex I (IACS-010759) and Complex II (TTFA, SDHC R72C mutant) to evaluate sensitization of resistant MM.
• Analysis of the ATF4-BIM/NOXA axis in response to ETC inhibition.

Main Results:

• Venetoclax-sensitive MM shows reduced mitochondrial respiration and lower ETC Complex I and II activities.
• Inhibition of Complex I or Complex II independently sensitizes venetoclax-resistant MM.
• ETC inhibition enhances BCL-2 dependence and primes cells via the ATF4-BIM/NOXA axis.
• Succinate ubiquinone reductase (SQR) activity correlates with venetoclax sensitivity in patient samples, regardless of translocation status.

Conclusions:

• Reduced mitochondrial respiration and electron transport chain activity are key features of venetoclax-sensitive multiple myeloma.
• Targeting mitochondrial Complex I or II can overcome venetoclax resistance.
• Succinate ubiquinone reductase (SQR) activity is a potential functional biomarker for selecting MM patients for venetoclax therapy.