Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma

Area of Science:

• Oncology
• Cancer Metabolism
• Biochemistry

Background:

• Metabolic reprogramming is a hallmark of cancer, contributing to tumor growth, metastasis, and therapeutic resistance.
• Overcoming resistance to targeted therapies, such as Bruton's tyrosine kinase (BTK) inhibitors, is a critical unmet need in relapsed/refractory cancers.
• Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor outcomes, often developing resistance to standard treatments.

Purpose of the Study:

• To investigate the role of metabolic reprogramming in ibrutinib resistance in MCL.
• To evaluate the efficacy of targeting oxidative phosphorylation (OXPHOS) as a strategy to overcome ibrutinib resistance.

Main Methods:

• Genomic analyses of clinical MCL specimens to identify metabolic alterations.
• In vitro and in vivo studies using patient-derived MCL models resistant to ibrutinib.
• Treatment with IACS-010759, a small molecule inhibitor of mitochondrial complex I (OXPHOS).

Main Results:

• Metabolic reprogramming towards OXPHOS and glutaminolysis was associated with ibrutinib resistance in MCL.
• Inhibition of OXPHOS with IACS-010759 demonstrated significant anti-proliferative effects in vitro.
• IACS-010759 treatment led to marked tumor growth inhibition in vivo in ibrutinib-resistant MCL models.

Conclusions:

• Targeting OXPHOS represents a promising therapeutic strategy to overcome ibrutinib resistance in MCL.
• Metabolic pathway inhibition offers a viable approach to treating refractory hematological malignancies.
• This study highlights the potential of targeting cancer metabolism to resensitize tumors to existing therapies.