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Small Molecule Shows Marked Activity Against Ibrutinib-Resistant MCL

Caroline Seymour
Published: Friday, May 17, 2019

Michael Wang, MD

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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