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Review
. 2025 Sep:200:22-32.
doi: 10.1016/j.ygyno.2025.06.022. Epub 2025 Jul 17.

The RAS-MEK-ERK pathway in low-grade serous ovarian cancer

Elizabeth H Stover  1 , Elizabeth K Lee  1 , Geoffrey I Shapiro  1 , Joan S Brugge  2 , Ursula A Matulonis  1 , Joyce F Liu  3
Affiliations
Review

The RAS-MEK-ERK pathway in low-grade serous ovarian cancer

Elizabeth H Stover et al. Gynecol Oncol. 2025 Sep.

Abstract

Low-grade serous ovarian cancer (LGSC) is an uncommon subtype of epithelial ovarian cancer, often arising in association with serous borderline tumors (SBT). Compared to high-grade serous ovarian cancers, LGSCs often occur in younger patients and are relatively insensitive to platinum-based chemotherapy, though some patients with LGSC can benefit from hormonal therapies. Genomic studies have demonstrated that SBT and LGSC frequently harbor mutations in members of the RAS-MEK-ERK pathway, which can be targeted therapeutically. LGSC harbor mutations in KRAS (up to 54 %, primarily non-G12C mutations), NRAS, and BRAF. Treatment of recurrent LGSC with the MEK inhibitor trametinib demonstrated improved clinical outcomes relative to other treatment options (chemotherapy, hormonal therapy) in a phase 3 trial. Other MEK inhibitors have also shown efficacy in LGSC, with some studies demonstrating higher response rates in patients whose tumors harbor KRAS mutations. However, some trials of MEK inhibitors showed more limited benefit (e.g. binimetinib), and RAS pathway mutations do not always correlate with increased efficacy, highlighting the need for further clinical and translational research in RAS-MEK-ERK pathway targeted therapeutics. Current clinical trials are evaluating MEK inhibitor combinations such as MEK inhibitors plus inhibitors of poly (ADP-ribose) polymerase (PARP), AKT, PI3K, CDK4/6, or BCL2/BCL-XL. Novel approaches to targeting the RAS-MEK-ERK pathway include the RAF/MEK clamp avutometinib, which has been evaluated in combination with the FAK inhibitor defactinib, and this combination received United States Food and Drug Administration (FDA) accelerated approval in 2025. Multiple newly developed inhibitors of KRAS, including KRAS G12C or G12D inhibitors, as well as pan-RAS inhibitors, including RAS (ON) inhibitors such as RMC-6236, are being evaluated in solid tumors. These emerging strategies for inhibiting RAS-MEK-ERK pathway activity may offer new treatment options for patients with LGSC.

Keywords: Low grade serous ovarian cancer; RAS pathway; Targeted therapy.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: U.A.M. declares participation in scientific advisory boards (Allarity, NextCure, Abbvie, Immunogen, Profound Bio, Eisai, the Ovarian Cancer Research Alliance, Tango Therapeutics, Novartis, GSK, Daiichi Sankyo), participation in a data safety-monitoring board (Mural Oncology and Symphogen), and consulting (Merck). GIS has research funding from Merck KGaA/EMD-Serono, Tango Therapeutics, Bristol Myers Squibb, Merck & Co., Artios, Lilly and Pfizer. He has served on advisory boards for Merck KGaA/EMD-Serono, Circle Pharmaceuticals, Concarlo Therapeutics, Schrodinger, FoRx Therapeutics and Xinthera. He holds patents entitled, “Dosage regimen for sapacitabine and seliciclib,” and “Compositions and Methods for Predicting Response and Resistance to CDK4/6 inhibition.” EKL has received honoraria for advisory board participation from: Aadi Biosciences, Oncusp Therapeutics, and Genmab. J.F.L declares the following: Funding to Dana-Farber Cancer Institute for Trials on which I am the PI: 2× Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Impact Therapeutics, NextCure, Pheon, Pfizer, Regeneron, Seagen, SystImmune, Vigeo Therapeutics, Volastra, and Zentalis Pharmaceuticals. She also serves on the following: NRG: Ovarian Subcommittee co-chair and Tina's Wish: Scientific Advisory Board Co-Chair, consulting for Bristol Myers Squibb, Clovis Oncology, Genentech Roche, and Advisory Boards for: Astrazeneca, Daiichi-Sankyo, Eisai, Genentech/Roche, LoxoLilly, Regeneron, Revolulion Medicine, Zentalis pharmaceuticals, and Deciphera Pharmaceuticals.

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