Scientists discover why a powerful leukemia drug fails in most patients

Researchers from Rutgers Health and other institutions have discovered why a powerful leukemia drug eventually fails in most patients – and found a potential way to overcome that resistance.

Team members identified a protein that lets cancer cells reshape their energy-producing mitochondria in ways that protect them from venetoclax (brand name, Venclexta), a standard treatment for acute myeloid leukemia that often loses effectiveness after prolonged use.

Blocking that protein with experimental compounds in mice with human acute myeloid leukemia restored the drug's effectiveness and prolonged survival.

The findings, published in Science Advances, reveal an unexpected mechanism of drug resistance and suggest a new approach for one of the deadliest blood cancers in adults.

"We found that mitochondria change their shape to prevent apoptosis, a type of cell suicide induced by these drugs," said senior study author Christina Glytsou, an assistant professor at Rutgers' Ernest Mario School of Pharmacy and Robert Wood Johnson Medical School and a member of the Rutgers Cancer Institute's Pediatric Hematology and Oncology Research Center of Excellence (NJPHORCE).

Although venetoclax induces remission in many acute myeloid leukemia patients by triggering cancer cell death, resistance develops in nearly all cases. The five-year survival rate remains at 30% and the disease kills about 11,000 Americans each year.

Using electron microscopy and genetic screens, members of Glytsou's team discovered that treatment-resistant leukemia cells produce high levels of a protein called OPA1, which controls the internal structure of mitochondria. Cells with these elevated OPA1 levels develop tighter, more numerous folds in their mitochondrial membranes - compartments called cristae – that trap cytochrome c, a molecule that normally triggers cell death when released.

The researchers confirmed the finding by examining cells from leukemia patients. Those who had relapsed after treatment showed sharply narrower cristae than newly diagnosed patients, with the most pronounced changes in patients who had been treated with venetoclax.

To test whether they restore drug efficacy by blocking this structural change, team members used two experimental OPA1 inhibitors. In mice transplanted with human leukemia cells, combining the OPA1 inhibitors with venetoclax at least doubled survival time compared with venetoclax alone.

The combination worked across diverse leukemia subtypes, including cells with mutations in the p53 gene, which are strongly associated with treatment resistance and poor outcomes.

The OPA1 inhibitors also appear to work through additional mechanisms beyond restoring cell death pathways. The experiments revealed that cells lacking OPA1 become heavily dependent on the nutrient glutamine and vulnerable to ferroptosis, a different form of cell death driven by iron and lipid damage.

Tests in mice showed the compounds didn't harm normal blood cell production, a critical safety consideration for any potential leukemia treatment in humans.

The research is in early stages. The OPA1 inhibitors, developed by collaborators at the University of Padua in Italy, are lead compounds that require further refinement before human testing can begin.

"There is still some time to go through," Glytsou said, adding that a third generation of compounds may be needed to improve the drugs' solubility and other properties.

Still, the work offers a promising direction for treating resistant leukemia and potentially other cancers, said Glytsou, who is also a member of the cancer institute's cancer pharmacology and cancer metabolism and immunology research programs. 

OPA1 is overexpressed in multiple cancer types and associated with poor prognosis and therapy resistance in breast cancer, lung cancer and other malignancies.