From Discovery to Delivery: Charting Progress in Gynecologic Oncology, hosted by Ursula A. Matulonis, MD, brings expert insights into the most recent breakthroughs, evolving standards, and emerging therapies across gynecologic cancers. Dr Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilcon Family Chair at the Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In this episode, Dr Matulonis was joined by Elizabeth H. Stover, MD, PhD, a physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School. Together, they explored the biology and therapeutic relevance of the RAS/MAP kinase pathway in gynecologic cancers.

Dr Stover began by explaining that the RAS/MAP kinase pathway is a well-established oncogenic signaling cascade that regulates cancer cell proliferation, survival, and invasion. Advances in drug development are now making it possible to target multiple points along this pathway, including RAS itself, once considered “undruggable.”

Drs Matulonis and Stover emphasized that RAS/MAP kinase pathway alterations are relatively common across gynecologic malignancies, occurring in at least 20% of cases overall. Certain disease subtypes have particularly high prevalence, including low-grade serous ovarian cancer, mucinous ovarian cancer, and subsets of endometrial and cervical cancers. Clinically, activation of this pathway is generally associated with more aggressive disease and reduced sensitivity to conventional chemotherapy, although nuances exist.

The conversation also explored emerging therapeutic strategies targeting this pathway. Early developmental success with MEK inhibitors—such as trametinib (Mekinist), selumetinib (Koselugo), and binimetinib (Mektovi)—has translated to meaningful clinical benefit, particularly in low-grade serous ovarian cancer. More recently, combination approaches have shown promise, including the dual RAF/MEK inhibitor avutometinib paired with the FAK inhibitor defactinib (Avmapki Fakzynja Co-pack). This combination addresses adaptive resistance mechanisms and has generated improved response rates and disease control, leading to its May 2025 FDA approval in this setting.

Looking ahead, Dr Stover highlighted the development of direct RAS inhibitors as one of the most exciting advances in oncology. Dr Stover concluded by outlining key areas of ongoing research, including understanding differential sensitivity across tumor subtypes, identifying mechanisms of resistance, and optimizing combination strategies.

S17 Ep7: RAS/MAP Kinase Pathway Targeting Makes Strides in Gynecologic Cancer Management: With Ursula A. Matulonis, MD; and Elizabeth H. Stover, MD, PhD