Pharmacological OPA1 inhibition impairs cristae morphology and sensitizes human AML to apoptosis. Credit score: Science Advances (2025). DOI: 10.1126/sciadv.adx8662
Researchers from Rutgers Well being and different establishments have found why a strong leukemia drug finally fails in most sufferers—and located a possible solution to overcome that resistance.
Crew members recognized a protein that lets most cancers cells reshape their energy-producing mitochondria in ways in which defend them from venetoclax (model identify, Venclexta), an ordinary therapy for acute myeloid leukemia that always loses effectiveness after extended use.
Blocking that protein with experimental compounds in mice with human acute myeloid leukemia restored the drug’s effectiveness and extended survival.
The findings, printed in Science Advances, reveal an surprising mechanism of drug resistance and counsel a brand new strategy for one of many deadliest blood cancers in adults.
“We found that mitochondria change their shape to prevent apoptosis, a type of cell suicide induced by these drugs,” stated senior research creator Christina Glytsou, an assistant professor at Rutgers’ Ernest Mario Faculty of Pharmacy and Robert Wooden Johnson Medical Faculty and a member of the Rutgers Most cancers Institute’s Pediatric Hematology and Oncology Analysis Middle of Excellence (NJPHORCE).
Though venetoclax induces remission in lots of acute myeloid leukemia sufferers by triggering most cancers cell demise, resistance develops in almost all instances. The five-year survival charge stays at 30% and the illness kills about 11,000 Individuals annually.
Utilizing electron microscopy and genetic screens, members of Glytsou’s staff found that treatment-resistant leukemia cells produce excessive ranges of a protein referred to as OPA1, which controls the interior construction of mitochondria. Cells with these elevated OPA1 ranges develop tighter, extra quite a few folds of their mitochondrial membranes—compartments referred to as cristae—that entice cytochrome c, a molecule that usually triggers cell demise when launched.
The researchers confirmed the discovering by analyzing cells from leukemia sufferers. Those that had relapsed after therapy confirmed sharply narrower cristae than newly recognized sufferers, with essentially the most pronounced modifications in sufferers who had been handled with venetoclax.
To check whether or not they restore drug efficacy by blocking this structural change, staff members used two experimental OPA1 inhibitors. In mice transplanted with human leukemia cells, combining the OPA1 inhibitors with venetoclax not less than doubled survival time in contrast with venetoclax alone.
The mixture labored throughout numerous leukemia subtypes, together with cells with mutations within the p53 gene, that are strongly related to therapy resistance and poor outcomes.
The OPA1 inhibitors additionally seem to work by further mechanisms past restoring cell demise pathways. The experiments revealed that cells missing OPA1 grow to be closely depending on the nutrient glutamine and susceptible to ferroptosis, a unique type of cell demise pushed by iron and lipid injury.
Exams in mice confirmed the compounds did not hurt regular blood cell manufacturing, a essential security consideration for any potential leukemia therapy in people.
The analysis is in early levels. The OPA1 inhibitors, developed by collaborators on the College of Padua in Italy, are lead compounds that require additional refinement earlier than human testing can start.
“There is still some time to go through,” Glytsou stated, including {that a} third technology of compounds could also be wanted to enhance the medication’ solubility and different properties.
Nonetheless, the work provides a promising path for treating resistant leukemia and probably different cancers, stated Glytsou, who can also be a member of the most cancers institute’s most cancers pharmacology and most cancers metabolism and immunology analysis applications.
OPA1 is overexpressed in a number of most cancers varieties and related to poor prognosis and remedy resistance in breast most cancers, lung most cancers and different malignancies.
Extra data:
Sofia La Vecchia et al, Small-molecule OPA1 inhibitors reverse mitochondrial variations to beat remedy resistance in acute myeloid leukemia, Science Advances (2025). DOI: 10.1126/sciadv.adx8662
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