Targeting PI3Kγ/AKT1-OCT4/SOX2 Axis with Eganelisib Suppresses Tumor Growth and Prevents Ovarian Failure in Malignant Ovarian Germ Cell Tumors.

OBJECTIVE Malignant ovarian germ cell tumors (MOGCTs) predominantly affect children and young women. Cisplatin-based chemotherapy is effective but frequently causes premature ovarian failure (POF). The PI3K/AKT pathway drives both MOGCT pathogenesis and chemotherapy-induced ovarian damage, yet no strategy simultaneously targets both. This study investigates whether the selective PI3Kγ inhibitor eganelisib can exert dual antitumor and ovarian-protective effects by modulating the AKT1-OCT4/SOX2 axis.

METHODS In this study, we tried to observe eganelisib antitumor effects on the human embryonal carcinoma cell line NCCIT in vitro and in vivo. Ovarian fertility was assessed by estrous cycle, hormone levels, follicular development, embryonic development, and fertility outcomes in mice treated with eganelisib compared with cisplatin. AKT1 overexpression and knockdown were performed to validate functional dependency. Protein interactions between AKT1 and OCT4/SOX2 were evaluated by co-immunoprecipitation.

RESULTS In vitro, eganelisib suppressed NCCIT cell proliferation, migration, invasion, and stemness via AKT1-dependent disruption of the AKT1-OCT4/SOX2 axis. In vivo, eganelisib achieved antitumor efficacy comparable to cisplatin while preserving ovarian reserve, maintaining hormone balance, and protecting fertility. Mechanistically, eganelisib upregulated PTEN and enhanced GSK3β activity in the ovary without activating stress-related FOXO3/mTOR pathways.

CONCLUSION Selective PI3Kγ inhibition with eganelisib suggests that selective PI3Kγ inhibition may partially dissociate antitumor activity from gonadotoxicity by targeting the shared AKT1-OCT4/SOX2 signaling axis. This dual-purpose strategy offers a promising mechanism-based approach for fertility-concurrent cancer therapy in young patients with MOGCTs.