Researchers from Rutgers Health and other scientific centers have discovered why a popular leukemia treatment gradually loses its effectiveness in most patients, and have also proposed a potential way to overcome this resistance.

A New Mechanism of Therapy Resistance

During their study, the team identified a protein that enables cancer cells to alter the shape of their mitochondria—organelles responsible for producing cellular energy. These changes help protect the cells from the effects of venetoclax (brand name Venclexta), a widely used drug for treating acute myeloid leukemia. Over time, venetoclax often becomes less effective, making the disease harder to treat.

When researchers blocked this protein in mice with human acute myeloid leukemia, experimental compounds restored the effectiveness of venetoclax and increased the animals' survival. These findings, published in the journal Science Advances, reveal an unexpected mechanism of drug resistance and open new possibilities for treating one of the most dangerous types of blood cancer in adults.

The Role of Mitochondria and the OPA1 Protein

As explained by Associate Professor Kristina Glitza from Rutgers, mitochondria change their structure to prevent apoptosis—a process of programmed cell death triggered by drugs like venetoclax. While venetoclax can induce remission in many patients with acute myeloid leukemia, almost all eventually develop resistance to the treatment. The five-year survival rate for this disease remains around 30%, and it claims about 11,000 lives annually in the United States alone.

Using electron microscopy and genetic screening, Glitza's team found that therapy-resistant leukemia cells produce abnormally high levels of the OPA1 protein, which organizes the internal structure of mitochondria. Cells with elevated OPA1 form denser and more numerous folds (cristae) in the inner mitochondrial membrane, retaining cytochrome c. Normally, cytochrome c is released from mitochondria to initiate cell death.

Confirmation in Patient Samples

These conclusions were confirmed in samples from leukemia patients. In individuals who relapsed after therapy, the cristae were significantly narrower than in newly diagnosed patients, especially among those previously treated with venetoclax.

Prospects for Combination Therapy

To test whether inhibiting mitochondrial structural changes could restore treatment sensitivity, the team evaluated two experimental OPA1 inhibitors. In mice transplanted with human leukemia cells, adding OPA1 inhibitors to venetoclax at least doubled survival compared to venetoclax alone.

This combined approach proved effective across various leukemia subtypes, including forms with p53 mutations, which are typically associated with poor prognosis and pronounced drug resistance.

Additional Benefits of OPA1 Inhibitors

The results also showed that OPA1 inhibitors may offer benefits beyond restoring standard cell death pathways. Experiments demonstrated that cells lacking OPA1 become highly dependent on the nutrient glutamine and are vulnerable to ferroptosis—a type of cell death caused by iron-dependent lipid damage.

Importantly, studies in mice indicated that these compounds do not disrupt the development of normal blood cells, which is crucial for developing new leukemia treatments for humans.

Future Research Directions

This research is still in its early stages. The OPA1 inhibitors developed by colleagues at the University of Padua (Italy) are currently leading compounds and require further refinement before clinical trials can begin. According to Glitza, it may be necessary to create a third generation of compounds to improve solubility and other drug properties.

Nevertheless, Glitza believes this work points to a promising therapeutic direction for resistant forms of leukemia and potentially other cancers. OPA1 is overexpressed in several tumor types and is linked to poor prognosis and therapy resistance in breast, lung, and other malignancies.

The Rutgers Cancer Institute, in partnership with RWJBarnabas Health, is the only comprehensive cancer center in New Jersey accredited by the U.S. National Cancer Institute.