Research Identifies PRMT5 Enzyme as Key Factor in Ovarian Cancer Chemotherapy Resistance

Recent research conducted by scientists at Northwestern Medicine has uncovered critical insights into the mechanisms behind chemotherapy resistance in advanced ovarian cancer, as reported in the Journal of Clinical Investigation.

Ovarian cancer remains one of the leading causes of cancer-related fatalities among women in the United States, despite significant advancements in treatment over the years. A notable number of patients continue to experience recurrence of the disease and develop resistance to chemotherapy. According to Dr. Mazhar Adli, a prominent figure in the study, overcoming chemotherapy resistance poses a substantial challenge for medical professionals treating this form of cancer.

Dr. Adli indicated that while ovarian cancer may initially respond well to chemotherapy, it often quickly transitions to a resistant state. Understanding the cellular mechanisms that contribute to this resistance is crucial for developing more effective treatment strategies.

In previous studies, the research team identified elevated levels of the enzyme PRMT5 in chemotherapy-resistant ovarian cancer cells. The current investigation employed advanced techniques such as intracellular immunostaining and CRISPR screening to delve deeper into the role of PRMT5.

The findings revealed that the protein KEAP1 serves as a significant regulator of PRMT5. Under normal circumstances, KEAP1 binds to PRMT5, facilitating its degradation and ensuring balanced protein levels. However, in tumors resistant to treatment, this regulatory mechanism is disrupted, resulting in increased levels of PRMT5.

Further analysis demonstrated that PRMT5 influences the expression of stress response genes, creating a cellular environment that enhances drug resistance. This discovery underscores the complex interplay between tumor biology and drug response.

In an innovative approach, the researchers combined PRMT5 inhibitors with traditional chemotherapy agents, yielding promising results. The combination therapy significantly increased cancer cell death and inhibited tumor growth in murine models of ovarian cancer.

Dr. Adli emphasized that KEAP1 plays a crucial role in modulating stress responses in cancer cells. During chemotherapy, when cells are subjected to stress, the KEAP1 pathway becomes suppressed, leading to heightened levels of PRMT5 and contributing to resistance.

This study paves the way for potential combination therapies targeting PRMT5, which may represent a novel and effective treatment option for patients with advanced ovarian cancer. Dr. Adli expressed his optimism about the next steps, including the initiation of clinical trials to further evaluate the therapeutic potential of this approach.

As the research progresses, there are ongoing clinical trials assessing PRMT5 inhibitors as standalone treatments. However, the evidence suggests that combining these inhibitors with existing chemotherapy regimens may enhance their efficacy.

For further information, refer to the study titled High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in high-grade serous ovarian cancer, published in the Journal of Clinical Investigation.