Cancer researchers test how to regulate gene expression in cells to prevent drug resistance in cancer therapies.
By Tanvi Patil
Cancer therapies often develop drug resistance to medications, so what if there was a way to hijack this process to reinstate a therapeutic effect? Scientists from the Rutgers Cancer Institute recently discovered a new pathway to restore drug sensitivity in acute myeloid leukemia, the deadliest form of blood cancer in adults.
What is acute myeloid leukemia (AML)?
Acute myeloid leukemia (AML) is a form of blood cancer that originates from mutations in the white blood cells (WBCs) found in our bone marrow. WBCs play a crucial role in activating and monitoring our immune system, meaning any disruptions here will lead to heightened sensitivity to bacterial and viral infections. In the context of AML, these mutations allow the body to uncontrollably produce premature WBCs that do not develop properly. These WBCs eventually crowd the blood and bone marrow, leaving less space for healthy cells to exist.
According to the National Cancer Institute, less than a third of AML cases have a five-year survival rate after receiving treatment, and the disease is predicted to be responsible for 11,000 deaths in 2025 alone. These statistics showcase the need to design better treatments for controlling AML.
Inhibitor treatments for AML
Most therapies target cancer by inducing a cell death process called apoptosis. They often involve inhibiting proteins that allow the cell to grow and divide uncontrollably. In AML, BCL-2, IDH, and FLT3 inhibitors are among the most common forms of treatment. While each of these proteins control different processes allowing cancerous cells to thrive, they share the same end result of apoptosis when inhibited. Specifically, BCL-2 proteins inhibit apoptosis by preventing pro-apoptotic markers from being released by a subcellular structure called the mitochondria. These pro-apoptotic markers are crucial for inducing cell death because they act as a “go signal” for the cell’s machinery to start dismantling the cell, thus their absence prevents cancer cells from inducing apoptosis.
The study at the Rutgers Cancer Institute focused on investigating venetoclax (a type of BCL-2 inhibitor) resistance. Venetoclax restores the cell death pathway in cancer cells by inactivating BCL-2 proteins. However, drug resistance has almost always been observed in patients treated with venetoclax. The scientists conducted genetic screens to identify that the OPA1 gene plays a crucial role in maintaining mitochondrial function in AML that is resistant to venetoclax. In particular, they discovered the OPA1 gene is overexpressed, which tightens the mitochondria and prevents it from releasing the pro-apoptotic markers in cancerous cells. We can also think of this as a suitcase with a lock and a zip. The lock is our BCL-2 protein and the zip is our OPA1 gene. We can see that even when the bag is unlocked (the BCL-2 protein is inactivated by venetoclax), the zipper is still closed (OPA1 gene is overexpressed), and this prevents all of our belongings (pro-apoptotic markers) from falling out!
Hijacking drug resistance
Given this mechanism, the scientists created an inhibitor for the OPA1 gene called MYLS22. Additional testing also revealed controlling gene expression through an inhibitor was more efficient than completely knocking out (blocking) the gene. They introduced human AML cells into mice, and treated them with MYLS22, venetoclax, or a combination of the two and conducted survival studies. Overall, their findings suggest mice treated with both venetoclax and MYLS22 had a higher cancer cell clearance rate, which allowed the mice to live longer.
The study also revealed OPA1 gene regulation renders the cell reliant on glutamine (a form of energy) which allows cancerous cells to persist but not divide. The scientists further explored this new level of complexity by introducing the protein inhibitor CB-839 to prevent the use of glutamine. Now, they treated mice carrying human AML with CB-839 to block glutamine usage, MYLS22 to inhibit the OPA1 gene, venetoclax to support apoptosis, or a combination of the three. Their findings from this experiment imply mice treated with a combination of CB-839, MYLS22, and venetoclax had the highest cancer cell clearance rate.
The future of OPA1 inhibitors
It is clear that new methods to combat drug resistance in cancer are coming to the front lines of biotechnology. From cancer vaccines to the drug cocktails discussed here, we will see therapies in the future that involve annexing normal processes for treating AML and other cancers. However, it is important to note biological cells are highly dynamic and our understanding of their internal processes remains incomplete. Thus, while this study proposes unique perspectives in hijacking known therapy mechanisms to circumvent drug resistance, it will still be a while before technology like this can enter the market.
This study was published in the peer-reviewed journal Science Advances.
References
Acute Myeloid Leukemia—Cancer Stat Facts. (n.d.). National Cancer Institute. Retrieved October 23, 2025, from https://seer.cancer.gov/statfacts/html/amyl.html
La Vecchia, S., Doshi, S., Antonoglou, P., Kundu, T., Al Santli, W., Avrampou, K., Witkowski, M. T., Pellattiero, A., Magrin, F., Ames, K., Verma, A., Gritsman, K., Su, X., Mattarei, A., Aifantis, I., Scorrano, L., & Glytsou, C. (2025). Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia. Science Advances, 11(42), eadx8662. https://doi.org/10.1126/sciadv.adx8662
Tsujimoto, Y. (1998). Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria? Genes to Cells, 3(11), 697–707. https://doi.org/10.1046/j.1365-2443.1998.00223.x.
Featured image: Photomicrograph of a bone marrow specimen extracted from a patient diagnosed with acute myeloid leukemia (AML), showing an overabundance of abnormal, immature white blood cells as they look pre-treatment. From the CDC’s Public Image Health Library.
About the Author
Tanvi Patil recently graduated from the University of Colorado Boulder with a B.S. in Chemical and Biological Engineering. Beyond exciting science, she enjoys wheel throwing pottery, exploring new cafes, and photography.
