Investigational Drug May Combat Ibrutinib Resistance in Mantle Cell Lymphoma

A newly-developed drug may help overcome resistance to treatment with ibrutinib in patients with mantle cell lymphoma (MCL), according to a study published in Science Translational Medicine.

MCL, a B-cell malignancy, often responds to initial treatment with ibrutinib, a Bruton’s tyrosine kinase inhibitor. However, patients can develop resistance to treatment with ibrutinib, although the cause of this resistance is not yet fully understood.

The drug, IACS-10759, is currently in phase 1 clinical trials for acute myeloid leukemia, as well as for solid tumors and lymphoma. IACS-10759 was the first drug to be developed from concept to clinical trial by MD Anderson’s Therapeutics Discovery division.

For the study, the authors developed an ibrutinib-resistant B-cell lymphoma mouse model to examine the link between metabolic reprogramming and cancer cell growth, metastasis, and therapeutic resistance. The findings indicated that metabolic reprogramming toward glycolysis and oxidative phosphorylation (OXPHOS), 2 key metabolic processes that help support the growth and survival of cancer cells, was associated with ibrutinib resistance, according to the researchers.

The study showed that these drug-resistant cells can be targeted with the clinically applicable small molecule, which targets complex I of the mitochondrial electron transport chain as demonstrated in the patient-derived model, the authors wrote.

“Inhibition of OXPHOS with IACS-10759 results in marked growth inhibition in vivo and in vitro in ibrutinib-resistant, patient-derived cancer models,” lead study author Michael Wang, MD, professor of Lymphoma & Myeloma, said in a press release.

Co-senior author Linghua Wang, PhD, assistant professor of Genomic Medicine, emphasized the urgent need to identify alternative therapies to MCL, especially since the 1-year survival rate for patients after relapse on ibrutinib is 22%.

These findings, Dr Wang said, support the exploitation of active cancer metabolic pathways, especially OXPHOS and glutaminolysis, to improve clinical outcomes for MCL and other lymphomas.

“This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies,” the authors concluded in the study.

References

Zhang L, Yao Y, Zhang S, et al. Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Science Translational Medicine. Doi: 10.1126/scitranslmed.aau1167

Study shows MD Anderson-developed drug effective in overcoming ibrutinib resistance in mantle cell lymphoma [news release]. MD Anderson Cancer Center. https://www.mdanderson.org/newsroom/study-shows-md-anderson-developed-drug-effective-in-overcoming-ibrutinib-resistance-in-mantle-cell-lymphoma.h00-159303045.html

. Accessed May 9, 2019.