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

TLDR

Metabolic reprogramming drives cancer growth, metastasis, and therapeutic resistance, and targeting dysregulated metabolic pathways to overcome resistance remains a critical but challenging clinical need. The study seeks to identify metabolic vulnerabilities that can be targeted to overcome ibrutinib resistance in mantle cell lymphoma. Using genomic analyses of clinical specimens, the authors linked OXPHOS and glutaminolysis reprogramming to ibrutinib resistance in mantle cell lymphoma. Inhibition of OXPHOS with the complex I inhibitor IACS‑010759 markedly suppressed growth of ibrutinib‑resistant mantle cell lymphoma models in vitro and in vivo, supporting metabolic targeting as a viable strategy against refractory cancers.

Abstract

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.