Enzyme Drives Treatment Resistance in Ovarian Cancer

Northwestern Medicine scientists have identified a key driver of chemotherapy resistance in advanced ovarian cancer, according to a study published in the Journal of Clinical Investigation.

Ovarian cancer is one of the leading causes of cancer deaths among women in the U.S., according to the American Cancer Society. Although treatments have improved greatly in recent decades, a large subset of patients experience cancer recurrence and develop chemotherapy resistance, said Mazhar Adli, PhD, the Thomas J. Watkins Memorial Professor of Tumor Genomics and an assistant professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine, who was senior author of the study.

“Chemotherapy resistance is the biggest clinical challenge for physicians to treat this type of cancer,” Adli said. “Initially, it’s very sensitive, but quickly it becomes chemoresistant. We need to figure out how the cells become chemoresistant, why they’re becoming chemoresistant and what kind of molecular mechanisms are enabling these cells to survive under harsh chemo treatments.”

Previous research from the Adli laboratory showed an abundance of PRMT5 — an enzyme known for its role in regulating gene expression — in chemotherapy-resistant ovarian cancer. In the current study, Adli and his collaborators employed intracellular immunostaining and CRISPR screening to better understand PRMT5’s role.

The scientists found that the protein KEAP1 is a key regulator of PRMT5, according to the findings. Under normal conditions, KEAP1 binds to PRMT5 and initiates its degradation, maintaining balanced protein levels. However, in treatment-resistant tumors, this regulation is disrupted, leading to elevated PRMT5 levels.

Further experiments found that PRMT5 influences the activity of stress response genes, fostering a cellular environment that supports drug resistance, according to the findings.

Finally, investigators combined PRMT5 inhibitors with chemotherapy drugs and found that the treatment increased cancer cell death and reduced tumor growth in mice with ovarian cancer.

“It turns out that KEAP1 is one of the regulators of stress response in these cells,” said Adli, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “If cells are under stress, then they suppress this KEAP1 pathway. The chemotherapy creates stress on the cells, KEAP1 gets suppressed and then PRMT5 becomes upregulated.”

The study establishes combination treatment targeting PRMT5 as a potentially promising therapy option for ovarian cancer, Adli said.

“The next step, I think, is to start a clinical trial,” Adli said. “We have shown that this is a really therapeutically exploitable target, and we have several good inhibitors for this one. We show that we need to combine these inhibitors with existing chemo to make them really therapeutically relevant. There are currently clinical trials underway testing the inhibitors alone, and we think testing them alone may not be as effective.”

The study was supported by the National Cancer Institute and National Institutes of Health grants R01CA267544 and U54CA268084.