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

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.