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Published on: August 2, 2024
Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma
Kewei Zheng1, Guanqin Jin1, Rui Cao2
1Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
Purpose:
Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC.
Methods:
In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects.
Results:
WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis.
Conclusion:
This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.
Insights
WX390, a PI3K/mTOR inhibitor, combined with cisplatin, shows synergistic effects against ovarian clear cell carcinoma (OCCC). This combination effectively suppresses tumor growth and enhances chemotherapy sensitivity in OCCC models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian clear cell carcinoma (OCCC) presents a significant clinical challenge due to its high malignancy, chemotherapy resistance, and poor prognosis.
- The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in the progression and adverse outcomes of various cancers, including OCCC.
Purpose of the Study:
- To investigate the combined therapeutic effects of WX390, a dual PI3K/mTOR inhibitor, and cisplatin on ovarian clear cell carcinoma (OCCC).
- To elucidate the molecular mechanisms underlying the efficacy of this combination therapy in preclinical OCCC models.
Main Methods:
- In vitro studies using OCCC cell lines (ES2, OVISE) and in vivo experiments with patient-derived xenograft (PDX) models.
- Assessment of cell proliferation, apoptosis, cell cycle dynamics, and pathway inhibition via Western blot and RNA-sequencing.
Main Results:
- WX390 demonstrated significant inhibition of OCCC cell proliferation and induction of apoptosis.
- The combination of WX390 and cisplatin (CDDP) exhibited synergistic effects, enhancing OCCC cell sensitivity to chemotherapy and suppressing tumor growth in PDX models.
- WX390 effectively inhibited the PI3K/AKT/mTOR pathway, disrupted autophagy, altered cell cycle progression, and induced apoptosis.
Conclusions:
- WX390 shows considerable efficacy in preclinical OCCC models, both as a single agent and in combination with cisplatin.
- These findings provide a strong rationale for developing WX390-based therapeutic strategies for ovarian clear cell carcinoma.
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