Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Xinran Li, Victor C.Y. Mak, Yuan Zhou, Chao Wang, Esther S.Y. Wong, Rakesh Sharma, Yiling Lu, Annie N.Y. Cheung, Gordon B. Mills, Lydia W.T. Cheung

    Research output: Contribution to journalArticle

    3 Scopus citations

    Abstract

    Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

    Original languageEnglish (US)
    Article number716
    JournalNature communications
    Volume10
    Issue number1
    DOIs
    StatePublished - Dec 1 2019

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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    Li, X., Mak, V. C. Y., Zhou, Y., Wang, C., Wong, E. S. Y., Sharma, R., Lu, Y., Cheung, A. N. Y., Mills, G. B., & Cheung, L. W. T. (2019). Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer. Nature communications, 10(1), [716]. https://doi.org/10.1038/s41467-019-08574-7