Targeting RAS–RAF–MEK–ERK signaling in mucinous ovarian cancer: a translational evidence synthesis and clinical framework
Mucinous ovarian cancer is a rare and molecularly distinct sub-type of epithelial ovarian cancer, characterized by intrinsic resistance to cytotoxic chemotherapy and poor prognosis in advanced stages, with a median overall survival of 12 to 34 months. Its low incidence (<3% of advanced epithelial ovarian cancers) limits the feasibility of large-scale clinical trials, underscoring the need for molecularly informed therapeutic strategies. Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway (most commonly through KRAS mutations [50%-65%] and near-universal MAPK hyperactivation) constitutes a defining feature of mucinous ovarian cancer biology and a rational therapeutic target. Despite this, there are no clinical data specifically evaluating MAPK-targeted therapies to date. Insights from other KRAS-driven malignancies reveal major challenges, including adaptive resistance, activation of compensatory signaling pathways (eg, PI3K/AKT), and intratumoral heterogeneity. This review synthesizes translational evidence for MAPK pathway targeting in mucinous ovarian cancer and proposes a clinical framework for treatment selection by integrating KRAS/MAPK activation with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) signaling, PI3K pathway alterations, and tumor-immune features. As comprehensive molecular profiling advances, integrated targeting of the rat sarcoma-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (RAS-RAF-MEK-ERK) cascade may offer promising and urgently needed therapeutic strategies for this rare malignancy.