Dr Liu on the Rationale for Targeting Wee1 in Ovarian Cancer

Joyce F. Liu, MD, MPH, associate chief and director of clinical research, Division of Gynecologic Oncology, associate clinical research officer, Dana-Farber Cancer Institute; associate professor of medicine at Harvard Medical School, discusses the role of Wee1 in cell cycle regulation and the rationale for developing therapies that inhibit this protein in ovarian cancer.

Ovarian cancer is now recognized as a heterogeneous disease encompassing various subtypes, each with distinct molecular characteristics. One notable feature observed in certain ovarian cancer subtypes is the overexpression of cyclin E, a protein that plays a crucial role in regulating the cell cycle, Liu states. Cyclin E overexpression accelerates cell progression through the G1/S checkpoint, resulting in heightened replication stress within the cells, she expands.

The cell cycle is highly controlled to ensure proper cell division, and one key regulatory checkpoint is the G2/M checkpoint, which is negatively regulated by the protein Wee1, Liu explains. Cells transitioning from G1 to the S phase and then towards mitosis encounter the G2/M checkpoint, where cells with DNA damage are prevented from entering the M phase. In cases of cyclin E amplification or high replication stress, cells become reliant on the G2/M checkpoint for proper division, Liu states. Wee1 inhibitors disrupt this regulatory checkpoint, allowing cells to bypass the G2/M arrest prematurely and enter mitosis, she says. However, cells that are not adequately prepared for division may undergo mitotic catastrophe, a form of cell death triggered by aberrant mitosis, Liu notes.

Ovarian cancers characterized by high cyclin E levels, often due to CCNE1gene amplification or other mechanisms, may be particularly vulnerable to therapies targeting the G2/M checkpoint, Liu emphasizes. By targeting the function of Wee1, these therapies can exploit the dependency of cyclin E-overexpressing cancer cells on the G2/M checkpoint, inducing mitotic catastrophe and potentially inhibiting tumor growth, Liu explains.

Understanding the molecular underpinnings of ovarian cancer subtypes, such as those exhibiting cyclin E dysregulation, enables the development of targeted therapies aimed at exploiting specific vulnerabilities within ovarian cancer cells. This personalized approach holds promise for improving treatment outcomes and advancing precision medicine in ovarian cancer management.