Michael Wang, MD
Preclinical data suggest that the small molecule IACS-10759, which targets the oxidative phosphorylation (OXPHOS) and glutaminolysis pathways, may play a critical role in overcoming resistance to ibrutinib (Imbruvica) in mantle cell lymphoma (MCL).1,2
In the translational study published in Science Translational Medicine
, results showed that metabolic reprogramming through these pathways enables tumor growth and survival. By inhibiting OXPHOS, researchers demonstrated marked growth inhibition in vivo and in vitro, in ibrutinib-resistant, patient-derived xenograft (PDX) mouse models. Little effect was observed in ibrutinib-sensitive MCL cell lines.
The inhibitor of electron transport chain (ETC) complex I significantly reduced ETC complex I activity in an in vitro enzymatic assay in ibrutinib-resistant MCL cell lines after treatment (P
= .0041). The oxygen consumption rate was also reduced in the ibrutinib-resistant MCL cell lines compared with ibrutinib-sensitive MCL cell lines.
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