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 Mills, Jean J. Zhao

Research output: Contribution to journalArticle

29 Citations (Scopus)

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
Externally publishedYes

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Genetic Models
Endometrial Neoplasms
Phosphatidylinositol 3-Kinase
Neoplasms
Survival
Penetrance
Epithelium

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A genetic mouse model of invasive endometrial cancer driven by concurrent loss of pten and Lkb1 is highly responsive to mTOR inhibition. / Cheng, Hailing; Liu, Pixu; Zhang, Fan; Xu, Erbo; Symonds, Lynn; Ohlson, Carolynn E.; Bronson, Roderick T.; Maira, Sauveur Michel; Tomaso, Emmanuelle Di; Li, Jane; Myers, Andrea P.; Cantley, Lewis C.; Mills, Gordon; Zhao, Jean J.

In: Cancer Research, Vol. 74, No. 1, 01.01.2014, p. 15-23.

Research output: Contribution to journalArticle

Cheng, H, Liu, P, Zhang, F, Xu, E, Symonds, L, Ohlson, CE, Bronson, RT, Maira, SM, Tomaso, ED, Li, J, Myers, AP, Cantley, LC, Mills, G & Zhao, JJ 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, vol. 74, no. 1, pp. 15-23. https://doi.org/10.1158/0008-5472.CAN-13-0544
Cheng, Hailing ; Liu, Pixu ; Zhang, Fan ; Xu, Erbo ; Symonds, Lynn ; Ohlson, Carolynn E. ; Bronson, Roderick T. ; Maira, Sauveur Michel ; Tomaso, Emmanuelle Di ; Li, Jane ; Myers, Andrea P. ; Cantley, Lewis C. ; Mills, Gordon ; Zhao, Jean J. / A genetic mouse model of invasive endometrial cancer driven by concurrent loss of pten and Lkb1 is highly responsive to mTOR inhibition. In: Cancer Research. 2014 ; Vol. 74, No. 1. pp. 15-23.
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