Targeting on the PI3K/mTOR: a Potential Treatment Strategy for Clear Cell Ovarian Carcinoma

Overview

Journal Cancer Chemother Pharmacol

Date 2025 Jan 10

PMID 39792198

Authors

Kewei Zheng

Guanqin Jin

Rui Cao

Yi Gao

Jing Xu

Ranran Chai

Yu Kang

Affiliations

Soon will be listed here.

Abstract

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.

References

Hsieh A, Liu Y, Edlind M, Ingolia N, Janes M, Sher A . The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012; 485(7396):55-61. PMC: 3663483. DOI: 10.1038/nature10912. View

Su J, He T, You J, Cao J, Wang Q, Cao S . Therapeutic effect and underlying mechanism of Shenkang injection against cisplatin-induced acute kidney injury in mice. J Ethnopharmacol. 2022; 301:115805. DOI: 10.1016/j.jep.2022.115805. View

Homma K, Suzuki K, Sugawara H . The Autophagy Database: an all-inclusive information resource on autophagy that provides nourishment for research. Nucleic Acids Res. 2010; 39(Database issue):D986-90. PMC: 3013813. DOI: 10.1093/nar/gkq995. View

Anglesio M, Carey M, Kobel M, MacKay H, Huntsman D . Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynecol Oncol. 2011; 121(2):407-15. DOI: 10.1016/j.ygyno.2011.01.005. View

Glick D, Barth S, Macleod K . Autophagy: cellular and molecular mechanisms. J Pathol. 2010; 221(1):3-12. PMC: 2990190. DOI: 10.1002/path.2697. View

De Leo A, Santini D, Ceccarelli C, Santandrea G, Palicelli A, Acquaviva G . What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors. Diagnostics (Basel). 2021; 11(4). PMC: 8070731. DOI: 10.3390/diagnostics11040697. View

Shoji T, Tatsuki S, Abe M, Tomabechi H, Takatori E, Kaido Y . Novel Therapeutic Strategies for Refractory Ovarian Cancers: Clear Cell and Mucinous Carcinomas. Cancers (Basel). 2021; 13(23). PMC: 8656608. DOI: 10.3390/cancers13236120. View

Cantrell D . Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 2001; 114(Pt 8):1439-45. DOI: 10.1242/jcs.114.8.1439. View

Liang X, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H . Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999; 402(6762):672-6. DOI: 10.1038/45257. View

10.

Kennedy A, Biscotti C, HART W, Webster K . Ovarian clear cell adenocarcinoma. Gynecol Oncol. 1989; 32(3):342-9. DOI: 10.1016/0090-8258(89)90637-9. View

11.

Hashiguchi Y, Tsuda H, Inoue T, Berkowitz R, C Mok S . PTEN expression in clear cell adenocarcinoma of the ovary. Gynecol Oncol. 2005; 101(1):71-5. DOI: 10.1016/j.ygyno.2005.09.047. View

12.

Itamochi H, Oishi T, Oumi N, Takeuchi S, Yoshihara K, Mikami M . Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. Br J Cancer. 2017; 117(5):717-724. PMC: 5572180. DOI: 10.1038/bjc.2017.228. View

13.

Caumanns J, Berns K, Wisman G, Fehrmann R, Tomar T, Klip H . Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma. Clin Cancer Res. 2018; 24(16):3928-3940. PMC: 6098697. DOI: 10.1158/1078-0432.CCR-17-3060. View

14.

Zhang Q, Yan H, Wang J, Cui S, Wang X, Jiang Y . Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1. Oncotarget. 2016; 7(29):46127-46141. PMC: 5216786. DOI: 10.18632/oncotarget.10060. View

15.

Wiegand K, Shah S, Al-Agha O, Zhao Y, Tse K, Zeng T . ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010; 363(16):1532-43. PMC: 2976679. DOI: 10.1056/NEJMoa1008433. View

16.

Guan B, Wang T, Shih I . ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res. 2011; 71(21):6718-27. PMC: 3206175. DOI: 10.1158/0008-5472.CAN-11-1562. View

17.

Kim S, Lee J, Lee M, Kim H, Chung H, Kim J . Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing. Gynecol Oncol. 2017; 148(2):375-382. DOI: 10.1016/j.ygyno.2017.12.005. View

17.

Zhang R, Liu C, Niu Y, Jing Y, Zhang H, Wang J . MicroRNA-128-3p regulates mitomycin C-induced DNA damage response in lung cancer cells through repressing . Oncotarget. 2017; 8(35):58098-58107. PMC: 5601636. DOI: 10.18632/oncotarget.12300. View

18.

Yang Y, Wang X, Yang J, Duan J, Wu Z, Yang F . Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC. Cancer Manag Res. 2019; 11:4931-4946. PMC: 6549766. DOI: 10.2147/CMAR.S207329. View

19.

Yamamoto S, Tsuda H, Takano M, Tamai S, Matsubara O . Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Mod Pathol. 2011; 25(4):615-24. DOI: 10.1038/modpathol.2011.189. View