The phosphoproteome of ovarian carcinoma delineates signaling signatures and potentially druggable targets across histotype stages

Abstract Ovarian malignancy is the most lethal gynecologic tumor, with an 80% relapse rate and 47% five-year survival. Epithelial ovarian cancer (EOC), the most common form, comprises five major histotypes with distinct clinicopathological characteristics, yet treatment still relies largely on cytoreductive surgery and platinum-based chemotherapy. Phosphoproteomics enables the mapping of protein phosphorylation, a key hallmark of cellular signaling. This study aimed to define phosphoproteomic-based ovarian cancer subgroups and assess their relationships with pathway activation patterns, patient prognosis, and therapeutic relevance. We analyzed the phosphoproteome of four major EOC histotypes from 180 patients. Dysregulated phosphosites critical for carcinogenesis were identified, including NUCKS1:S181, WWTR1:S89, and SRRM2:T1880. Kinase activity revealed histotype-specific CDK1/2 signatures linked to EOC-related signaling pathways. Prognostic phosphosites displayed stage- and histotype-dependent patterns. Collectively, these findings elucidate signaling cascades driving disease progression and identify potential therapeutic targets in early and advanced EOC, supporting future efforts toward the development of histotype-specific treatment strategies.