A genetic mouse model of invasive endometrial cancer driven by concurrent loss of pten and Lkb1 is highly responsive to mTOR inhibition

Hailing Cheng, Pixu Liu, Fan Zhang, Erbo Xu, Lynn Symonds, Carolynn E. Ohlson, Roderick T. Bronson, Sauveur Michel Maira, Emmanuelle Di Tomaso, Jane Li, Andrea P. Myers, Lewis C. Cantley, Gordon B. Mills, Jean J. Zhao

    Research output: Contribution to journalArticle

    32 Scopus citations

    Abstract

    Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors.

    Original languageEnglish (US)
    Pages (from-to)15-23
    Number of pages9
    JournalCancer Research
    Volume74
    Issue number1
    DOIs
    StatePublished - Jan 1 2014

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Cheng, H., Liu, P., Zhang, F., Xu, E., Symonds, L., Ohlson, C. E., Bronson, R. T., Maira, S. M., Tomaso, E. D., Li, J., Myers, A. P., Cantley, L. C., Mills, G. B., & Zhao, J. J. (2014). A genetic mouse model of invasive endometrial cancer driven by concurrent loss of pten and Lkb1 is highly responsive to mTOR inhibition. Cancer Research, 74(1), 15-23. https://doi.org/10.1158/0008-5472.CAN-13-0544