A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition

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 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.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Mice with homozygous endometrial LKB1 inactivation underwent diffuse malignant transformation of the entire endometrium with rapid extra uterine spread and death suggesting that LKB1 inactivation was sufficient to promote the development of invasive EC (Contreras et al 2010). In a mouse model of EC, dual loss of PTEN and LKB1 in the endometrial epithelium led to rapid development of advanced EEC with 100% penetrance and short host survival (Cheng et al 2014). Co et al (2014) analyzed LKB1 gene expression in low and high grade EECs and found that LKB1 is a direct transcriptional target of p53.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…13 Almost all AA SMGs identified in this study were found in patients with endometrioid UCEC, including 20 patients that were double-mutant for MTOR and PTEN. MTOR is thought to be overactive in endometrial cancers with inactive PTEN, 43 and as MTOR is a major posttranslational inhibitor of autophagy, it is tempting to speculate that autophagy may be less active in type I endometrioid tumors. It is noteworthy that we observed a recurrent truncating mutation (R1321*) in autophagy induction complex member RB1CC1 in 3 UCEC patients, along with a predicted damaging substitution (S93L) in 2 additional patients, suggesting autophagy induction may be compromised in these endometrioid UCEC patients.…”

Dissecting the signaling pathways that mediate cancer in PTEN and LKB1 double-knockout mice

“…Whereas the individual knockout of each gene causes only a low incidence of cancer, double knockouts markedly increase cancer incidence (1,2). However, the molecular mechanism by which their combined loss leads to cancer is not fully understood.…”